Effects of arteether on an auditory radial-arm maze task in rats

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.