Department of Safety Pharmacology, AstraZeneca R&D, SE-15185 Södertälje, Sweden.
Brain Res. 2010 Mar 19;1321:78-87. doi: 10.1016/j.brainres.2010.01.029. Epub 2010 Jan 25.
A large number of commercially available drugs are known to cause visual side effects in humans. Therefore, it would be advantageous to screen for alterations in visual function at a pre-clinical stage. Available methods, however, lack control for motivational and motoric side effects. The aim of the present study was therefore to develop a behavioural test to detect and quantify drug-induced visual side effects while simultaneously controlling for other side effects. We here present a novel model based on operant conditioning methodology with a food rewarded two-choice design to assess visual acuity and contrast sensitivity in rats. Rats were trained to discriminate between computer-generated sine-wave gratings and homogenous grey stimuli of equal luminance. They were subsequently tested with novel stimuli differing to training stimuli according to either spatial frequency or contrast. Finally, we tested how visual acuity was affected by oral administration of quinine HCl, a compound known to affect visual function in man. The rats learned to discriminate visual stimuli within 4-5weeks of twice daily training. A training procedure with moving stimuli achieved faster learning than with static stimuli. The visual detection threshold for discrimination of grating patterns decreased as a function of the contrast level, ranging from a spatial frequency of 0.8cycles/degree (c/d) at 100% contrast to 0.2c/d at 12.5%. Administration of quinine HCl was shown to affect the visual acuity threshold in a dose- and time dependent manner. In addition, response rate was affected by quinine administration but temporally isolated from the attenuation of visual acuity demonstrating that this model can separate the visual effects from motoric and motivational side effects.
大量市售药物已知可引起人类视觉副作用。因此，在临床前阶段筛选视觉功能的改变将是有利的。然而，现有的方法缺乏对动机和运动副作用的控制。因此，本研究的目的是开发一种行为测试方法，以在同时控制其他副作用的情况下检测和量化药物引起的视觉副作用。我们在这里提出了一种基于操作性条件反射方法的新型模型，采用食物奖励的双选择设计来评估大鼠的视力和对比敏感度。大鼠被训练区分计算机生成的正弦波光栅和具有相同亮度的均匀灰色刺激。然后，他们用与训练刺激不同的新刺激进行测试，根据空间频率或对比度进行测试。最后，我们测试了盐酸奎宁（一种已知会影响人类视觉功能的化合物）的口服给药如何影响视力。大鼠在每天两次训练的 4-5 周内学会了区分视觉刺激。与静态刺激相比，移动刺激的训练程序可实现更快的学习。对光栅模式进行区分的视觉检测阈值随着对比度水平的降低而降低，范围从 100%对比度下的 0.8 个/度（c/d）到 12.5%下的 0.2c/d。盐酸奎宁的给药显示出剂量和时间依赖性地影响视力阈值。此外，反应率受奎宁给药的影响，但与视力降低在时间上分离，证明该模型可以将视觉效果与运动和动机副作用分开。
