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An increasing body of research has focused on isolating factors that predict or alter individual differences in the behavioral and neural processes mediating the effects of abused drugs. Within this framework, the current report assessed individual differences and the locomotor effect of nicotine. Rats were screened for activity induced by a novel environment. Rats, which were more active to initial environment exposure, remained more active even after seven additional 30-min exposures to the same environment. Treatment with nicotine-di-D tartrate (1 mg/kg, sc) disrupted this effect. This nicotine disruption of individual differences occurred whether nicotine suppressed locomotor activity (initial administration) or stimulated locomotor activity (seventh and eighth administration). Mecamylamine (1 mg/kg), but not hexamethonium (10 mg/kg), completely blocked the suppressant and stimulant effects of nicotine. Further, mecamylamine restored the nicotine-induced disruption of individual differences; hexamethonium had no effect. This data pattern suggests that the disruptive effects of acute and chronic nicotine on individual differences were mediated by neural nicotinic acetylcholine (nACh) receptors.