A reduction in nicotinic receptors has been observed in brains of patients with Alzheimer's disease, and physostigmine, an indirect acting cholinergic agonist, has been suggested as a treatment of this disease. However, the effects of physostigmine treatment have not been thoroughly characterized. The central and peripheral effects of physostigmine were evaluated in C57BL/6 mice using a battery of behavioral and physiological tests that included respiratory rate, Y maze crossing and rearing activities, heart rate and body temperature. With the exception of the heart rate test, which was blocked by a peripheral muscarinic antagonist, all responses to physostigmine measured in the test battery seem to be mediated centrally. Sensitivity to physostigmine and to nicotine and oxotremorine were examined as were nicotinic and muscarinic receptors after continuous infusion of physostigmine. Mice (C57BL/6) continuously infused with physostigmine (0.1 mg/kg/h) for 10 days developed marked tolerance to physostigmine and exhibited a slight decrease in sensitivity to nicotine; sensitivity to oxotremorine was largely unaltered. Chronic physostigmine treatment resulted in a 62% inhibition of AChE activity and elicited a significant increase in the amount of L-[3H] nicotine binding in midbrain, hippocampus, striatum and colliculi; alpha-[125I]bungarotoxin and [3H]quinuclidinyl benzilatl binding were not changed. Although physostigmine treatment might partially reverse the reduction of brain nicotinic receptors seen with Alzheimer's disease, it is questionable whether it would be effective for a prolonged period since the up-regulated nicotinic receptors may not have normal function.