Genovese R F, Nguyen H A, Mog S R
Division of Neurosciences and Pathology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.
Physiol Behav. 2001 May;73(1-2):87-91. doi: 10.1016/s0031-9384(01)00462-0.
We evaluated the behavioral and neural toxicity of the artemisinin antimalarial compound, arteether (AE), using a novel radial-arm maze procedure. We have previously shown that AE can produce a distinctive pattern of neurotoxicity in the brainstem and that auditory nuclei are particularly vulnerable. Thus, we assessed performance which depended upon auditory processing. We trained rats to choose one of eight arms of a radial maze, depending upon which arm served as the source of a white noise stimulus. Correct responses produced food reinforcement while incorrect choices had no programmed consequences. When the task was acquired, AE (25 mg/kg/day; n=7) or oil vehicle (n=7) was administered (intramuscularly) for seven consecutive days. Behavioral sessions were conducted during the days of drug administrations and for 7 days following drug administrations. Subsequently, histopathology was conducted and a quantitative assessment of the nucleus trapezoideus was made. AE produced a progressive deficit in performance on the maze task. That is, accuracy decreased, choice latency increased, and the number of trials completed decreased. Moreover, the greatest deficits were observed during the period following drug administrations. AE-treated rats revealed marked damage in the nucleus trapezoideus. The damage included chromatolysis, necrosis, and gliosis. Vehicle-treated rats did not show performance deficits or neuropathology. These results extend earlier studies and show that AE can produce damage in the n. trapezoideus of rats, which is associated with performance deficits on a complex auditory task. Thus, the auditory radial-arm maze task is a useful tool for assessing AE-induced toxicity.
我们使用一种新颖的放射状臂迷宫程序评估了青蒿素抗疟化合物蒿乙醚（AE）的行为和神经毒性。我们之前已经表明，AE可在脑干中产生独特的神经毒性模式，并且听觉核特别容易受到影响。因此，我们评估了依赖听觉处理的行为表现。我们训练大鼠根据作为白噪声刺激源的是哪条臂来选择放射状迷宫的八条臂之一。正确反应会得到食物强化，而错误选择则没有预设后果。当大鼠学会该任务后，连续七天（肌肉内）给予AE（25毫克/千克/天；n = 7）或油性赋形剂（n = 7）。在给药期间以及给药后的7天进行行为测试。随后，进行组织病理学检查并对斜方体核进行定量评估。AE导致迷宫任务的表现逐渐下降。也就是说，准确性降低，选择潜伏期增加，完成的试验次数减少。此外，在给药后的时期观察到最大的缺陷。接受AE治疗的大鼠在斜方体核中显示出明显损伤。损伤包括染色质溶解、坏死和神经胶质增生。接受赋形剂治疗的大鼠未表现出行为缺陷或神经病理学变化。这些结果扩展了早期研究，表明AE可在大鼠的斜方体核中产生损伤，这与复杂听觉任务的表现缺陷有关。因此，听觉放射状臂迷宫任务是评估AE诱导毒性的有用工具。
