Pyridostigmine bromide (Pyr), the current drug of choice in the management of myasthenia gravis, has been suggested for use in Alzheimer's dementia, and as a prophylactic treatment for intoxication with organophosphate cholinesterase inhibitors. The present study was undertaken to evaluate the dose-response and time-course effects of acute oral administration of Pyr over a broad dose range (3-40 mg/kg) on the lever pressing of rats maintained under a multiple fixed-ratio (FR-20) time-out schedule of reinforcement for water reward. The drug produced a dose-dependent biphasic response depression in the overall rate of FR responding. Low doses of Pyr (less than or equal to 12 mg/kg) that caused no gross signs of toxicity only moderately decreased rates of responding, primarily due to a decrease in response rates. Whereas high doses of Pyr (greater than 24 mg/kg) which produced overt signs of peripheral cholinergic intoxication markedly suppressed overall responding, primarily due to cessation of responding. The lowest effective dose of performance disruption was 6 mg/kg, and the ED50 was calculated as 23.3 (17.9-28.7) mg/kg. The time-course data of performance disruption showed that low doses of Pyr (less than or equal to 12 mg/kg) had an onset latency within 40-80 min and a duration of 20-80 min, whereas high doses (greater than or equal to 24 mg/kg) had an onset latency of 20-40 min and a duration greater than 80 min. These results suggest the recommended human therapeutic or prophylactic regimen of 30-120.mg Pyr, orally taken each 8 hours, might adversely affect behavioral performance.