This study was undertaken to determine whether the biochemical changes in cholinergic systems produced by lead exposure result in corresponding changes in cholinergic sensitivity in vivo. Rats chronically exposed from weaning to 0, 50 or 150 ppm lead (Pb) acetate in drinking water were trained to discriminate the stimulus properties of a dose of 1.75 mg/kg of the muscarinic cholinergic agonist, arecoline, from saline, using standard operant food reinforced drug discrimination procedures. Following acquisition of the discrimination, various doses of arecoline, another muscarinic agonist, oxotremorine, a nicotinic agonist, nicotine, and the GABAA modulator, pentobarbital, were substituted for the arecoline training dose, and the ability of various doses of the muscarinic antagonist, atropine, to antagonize the discriminative stimulus properties of the 1.75 mg/kg dose of arecoline were examined. Arecoline and oxotremorine produced dose-related increases in drug lever responding, while pentobarbital produced a partial generalization that was not dose-related. Arecoline's stimulus properties were substantially antagonized by atropine. Pb exposure significantly increased sensitivity to oxotremorine but not to arecoline, and attenuated the ability of some doses of atropine to antagonize the stimulus properties of arecoline. These findings demonstrate altered cholinergic sensitivity in response to environmentally relevant levels of lead in blood, and raise the possibility of cholinergic system disturbances in the behavioral manifestations produced by lead exposure.