Locomotor activity was tested daily following cocaine injections across 21 consecutive days. Subjects were pretreated 30-min before testing with physiological saline, the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NAME), or the NMDA-receptor antagonist MK-801. Other rats received daily injections of physiological saline instead of cocaine just prior to testing. Rats pretreated with saline and injected daily with cocaine showed increased locomotor activity across the 21-day test period. L-NAME pretreatment depressed cocaine-stimulated locomotor activity, while MK-801 pretreatment increased locomotor activity. To test for behavioral sensitization to cocaine, rats were injected with cocaine 72 hours after their last daily injections. Sensitization was seen in saline pretreated subjects injected daily with cocaine compared to subjects injected daily with saline only, but both L-NAME and MK-801 pretreatment strongly attenuated cocaine sensitization. This finding is consistent with the proposed roles of nitric oxide and NMDA-receptors in cellular adaptation and learning.