These experiments examined the relationship between behavioral alterations and neurochemical changes in rats exposed repeatedly to disulfoton, an organophosphate cholinesterase inhibitor. Long-Evans rats were injected i.p. for 30 days with 0, 0.5,1, or 2 mg/kg of disulfoton in corn oil. Clinical signs and motor activity were measured during the course of repeated exposure. Cognitive function, as measured in the Morris water maze and passive avoidance procedures, was assessed near the end of the dosing regimen. Regional brain acetylcholinesterase (AChE) activity was measured during the course of dosing while total 3[H]-QNB binding sites were measured at the end of the behavioral experiments. Tolerance developed rapidly to the clinical signs produced by disulfoton, but not to the disulfoton-induced decrease in motor activity. Disulfoton affected acquisition of water maze performance, but had no effect on passive avoidance acquisition or retention. Repeated exposure to disulfoton significantly decreased brain AChE activity and 3[H]-QNB binding sites. These data indicate that, in spite of compensatory neurochemical changes that follow repeated exposure to disulfoton, tolerance develops to only some of the functional effects produced by this chemical.