Rationale

Benzodiazepines induce electroencephalography (EEG) changes in rodents and humans that are associated with distinct behavioral effects and have been proposed as quantitative biomarkers for GABA_A receptor modulation. Specifically, central EEG beta and occipital EEG delta activity have been associated with anxiolysis and sedation, respectively. The extent to which nonhuman primates show the same dose- and topography-dependent effects remained unknown.

Objectives

We aimed at establishing a nonhuman primate model for the evaluation of benzodiazepine EEG pharmacology.

Methods

Four adult male rhesus monkeys were prepared with fully implantable telemetry devices that monitored activity, peripheral body temperature, and contained two EEG (central and occipital), one electromyography (EMG), and one electrooculography channel. We investigated daytime alprazolam-induced changes in EEG spectral power, sleep–wake states, EMG activity, locomotor activity, and body temperature. Alprazolam (0.01–1.8 mg/kg, i.m.) or vehicle was administered acutely, and telemetry recording was conducted for 1 h.

Results

Daytime alprazolam dose-dependently increased central EEG power (including beta activity), increased occipital EEG delta power, and decreased occipital EEG alpha, theta, and sigma power. There was an ~8-fold difference in the potency of alprazolam to increase central EEG beta vs. occipital EEG delta activity (based on relative EEG power). The highest dose, which increased both central EEG beta and occipital EEG delta relative power, induced sedative effects (increased time spent in N1 and N2 sleep stages) and decreased peripheral body temperature and locomotor activity.

Conclusions

Alprazolam induces dose- and topography-dependent EEG changes in rhesus monkeys and provides a valuable model for studying benzodiazepine pharmacology.

中文翻译：

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阿普唑仑诱导的恒河猴脑电图谱功率变化：评估苯二氮卓类药物行为影响的转化模型

基本原理

苯二氮卓类药物会诱导啮齿动物和人类的脑电图 (EEG) 变化，这些变化与不同的行为效应相关，并且已被提议作为 GABA _A受体调节的定量生物标志物。具体而言，中央 EEG β 和枕叶 EEG δ 活动分别与抗焦虑和镇静有关。非人灵长类动物在多大程度上显示出相同的剂量和地形依赖性效应仍然未知。

目标

我们的目的是建立一个非人灵长类动物模型来评估苯二氮卓类 EEG 药理学。

方法

为四只成年雄性恒河猴准备了完全可植入的遥测设备，这些设备监测活动、周围体温，并包含两个脑电图（中央和枕骨）、一个肌电图 (EMG) 和一个眼电图通道。我们调查了白天阿普唑仑引起的 EEG 频谱功率、睡眠-觉醒状态、EMG 活动、运动活动和体温的变化。阿普唑仑 (0.01–1.8 mg/kg, im) 或载体被急性给药，遥测记录进行 1 小时。

结果

日间阿普唑仑剂量依赖性地增加中央 EEG 功率（包括 β 活动），增加枕叶 EEG delta 功率，并降低枕叶 EEG α、θ 和 sigma 功率。阿普唑仑增加中央 EEG β 与枕叶 EEG δ 活动的效力相差约 8 倍（基于相对 EEG 功率）。最高剂量增加了中央 EEG β 和枕叶 EEG δ 的相对功率，诱导了镇静作用（增加了在 N1 和 N2 睡眠阶段花费的时间）并降低了周围体温和运动活动。

结论

阿普唑仑在恒河猴中诱导剂量和地形图依赖性脑电图变化，并为研究苯二氮卓类药理学提供了一个有价值的模型。