The present study was designed to determine whether the muscarinic cholinergic antagonist scopolamine can prevent the expression and induction of sensitization to the locomotor-activating effects of cocaine. Rats received one daily injection of cocaine (20 mg/kg i.p.) for 5 days. Two days after withdrawal of pretreatment, rats were pretreated with scopolamine (3.0 mg/kg s.c) or its vehicle and challenged 15 min later with either saline or cocaine (20-30 mg/kg i.p.). In second set of experiments, scopolamine (3.0 mg/kg s.c) or its vehicle was given in combination with either saline or cocaine (20 mg/kg i.p.) for 5 days. Activity in response to saline and to cocaine (20 mg/kg i.p.) was assessed on day 7. The effects of acute administration of scopolamine (3.0 mg/kg s.c.) on cocaine-induced locomotor activity were also assessed. Acute administration of scopolamine increased both distance traveled and time spent in stereotypy. When scopolamine was administered 15 min prior to an acute injection of cocaine, a significant increase in the behavioral response to cocaine was seen. Daily injections of cocaine for 5 days produced sensitized behavioral responses to a subsequent cocaine challenge. Acute administration of scopolamine to animals preexposed and sensitized to cocaine did not disrupt the expression of sensitization to the locomotor and stereotypic effects of cocaine. In contrast, when scopolamine was given in combination with cocaine for 5 days, sensitization to the locomotor-activating effects of cocaine was prevented. These results suggest an important role of cholinergic muscarinic systems in mediating sensitization to the locomotor-activating effects of cocaine, which occurred after the repeated context-independent administration of this agent. In contrast, the enhanced stereotypic effects in response to the repeated administration of cocaine seem to be independent of alterations in muscarine cholinergic transmission.