Bilateral excitotoxic lesions of the nucleus basalis magnocellularis in rats were used along with testing in the water maze task to assess whether inhibition of acetylcholinesterase with physostigmine would reverse the lesion-induced impairment. Rats were lesioned bilaterally in stages using ibotenic acid and then behaviorally tested 3 weeks after surgery. Lesioned animals were administered one of three doses of physostigmine (0.06, 0.19, or 0.32 mg/kg) or vehicle solution 15 min prior to water maze testing. Sham lesioned animals injected with vehicle solution served as an untreated control group. Animals were tested for 5 consecutive days followed by 2 days off and then tested for 5 additional days. The rats were then sacrificed and their frontal cortex was assayed for choline acetyltransferase. The nucleus basalis magnocellularis lesion caused approximately a 27% depletion of choline acetyltransferase in the frontal cortex of these animals. The lesion also impaired the performance of the rats given vehicle solution as compared to untreated controls. Two doses (0.06 and 0.19 mg/kg) of physostigmine improved performance relative to lesioned controls. The lower dose, 0.06 mg/kg, improved performance more than the 0.19 mg/kg dose of physostigmine. The highest dose of physostigmine impaired water maze performance relative to lesioned controls. These data are discussed in relation to the cholinergic hypothesis of Alzheimer's disease and the potential therapeutic use of physostigmine.