Cocaine produces not only euphoric effects but also a wide range of detrimental effects, including seizures and lethality. The present study examined the involvement of the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptors and the dopamine D 1 and D 2 receptors in seizure activity and lethality observed following single and repeated injections of cocaine in ddY mice. Repeated injections of 60 mg/kg cocaine resulted in the development of sensitization to the convulsant effects of cocaine during an initial 3 or 4 days, followed by the development of tolerance at day 5 and day 6. Repeated injections of 90 mg/kg cocaine augmented the lethal effect of cocaine progressively over the course of treatment. Treatment with 0.1-0.4 mg/kg of the noncompetitive NMDA receptor antagonist, MK-801, prevented the development of sensitization to cocaine-induced seizures in a dose-dependent manner, and attenuated partially the cocaine-induced lethality. In contrast, treatment with 10-50 mg/kg of the dopamine D 2 receptor antagonist, sulpiride, had no effects on the development of sensitization and tolerance to cocaine-induced seizures. On the other hand, treatment with 0.1-0.5 mg/kg of the dopamine D 1 receptor antagonist, SCH 23390, not only prolonged the latency to 90 mg/kg cocaine-induced seizures but also delayed the development of sensitization to the convulsant effects of cocaine. The increased lethality observed following repeated injection of cocaine was unaffected by treatment with SCH 23390, but was severely aggravated by treatment with sulpiride. These results suggest that the development of sensitization to cocaine-induced seizures and lethality is primarily associated with NMDA receptor-mediated mechanisms, but that the dopamine D 1 and D 2 receptors may also be involved subordinately in cocaine-induced seizures and lethality, respectively, in mice.