The present study assessed the ability of N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801), to modulate neonatal cocaine-induced neurobehavioral changes in the rat. Sprague-Dawley rats were randomly assigned on postnatal day 0 (PND 0) to one of four treatment groups. Treatments began on PND 4 and continued until PND 10. Treatments consisted of an oral bolus of either cocaine HCl (40 mg/kg), (+)MK-801 (0.4 mg/kg), (+)MK-801 (0.4 mg/kg) followed 30 min later with cocaine HCl (40 mg/kg) or 0.9% saline. On PND 21, 30, 40 and 60, males and females were examined for stress response using the cold-water swim test. Cocaine-treated male and female rats exhibited significantly diminished tolerance to cold-water stress compared to control and MK-801/cocaine-treated groups. In addition, neonatal exposure to cocaine was associated with increased severity of motor symptoms (tail twitches, wet dog shaking and convulsions) following the administration of NMDA (35 mg/kg). Treatment groups were also tested for pain sensitivity using the tail flick (TF) and hot plate (HP) methods. The results indicated that neonatal cocaine exposure altered pain sensitivity in both tests. NMDA receptor binding studies showed a significant increase in receptor densities in the hippocampus and hypothalamus of the cocaine-treated group compared to control. MK-801 administered to rat pups before cocaine treatment blocked the increase in receptor density. The results indicated that neonatal cocaine exposure was associated with altered responses to NMDA, stress tolerance and pain sensitivity. Moreover, the pretreatment with NMDA receptor antagonist, MK-801, abolished or attenuated these cocaine-induced neurobehavioral changes.