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The United States Environmental Protection Agency and the Organization for Economic Cooperation and Development have recommended incorporating measurement of motor activity into routine toxicity studies to provide a screen for potential neurotoxic effects. However, there is little information on how to interpretate motor activity levels when an animal's clinical state is altered by systemic toxicity. Because systemic toxicity often includes nonspecific effects, such as reduced feed consumption, this physiologic condition was mimicked by limiting the feed of healthy rats to 10-15 g/rat/day and by limiting appetite through induction of endotoxemia. Injection of animals with endotoxin lowered motor activity by 50%. Combining feed restriction with endotoxin treatment resulted in reduced motor activity 2 days after injection, when signs of endotoxemia were not apparent. Animals treated with endotoxin but fed ad libitum had motor activity levels comparable to the control group 2 days after injection. The results suggest that motor activity levels can be altered by reduced feed consumption in the presence of subclinical systemic toxicity. Significant feed restriction in the absence of systemic toxicity appears unlikely to result in lowered motor activity levels.