The role of NMDA receptors in neonatal cocaine-induced neurotoxicity

The present study assessed the ability of N-methyl-D-aspartate (NMDA) recep tor antagonist, dizocilpine (MK-801), to modulate neonatal cocaine-induced neurobehavioral changes in the rat. Sprague-Dawley rats were randomly assig ned 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 respo nse using the cold-water swim test. Cocaine-treated male and female rats ex hibited 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 t witches, wet dog shaking and convulsions) following the administration of N MDA (35 mg/kg). Treatment groups were also tested for pain sensitivity usin g the tail flick (TF) and hot plate (HP) methods. The results indicated tha t neonatal cocaine exposure altered pain sensitivity in both tests. NMDA re ceptor binding studies showed a significant increase in receptor densities in the hippocampus and hypothalamus of the cocaine-treated group compared t o control. MK-801 administered to rat pups before cocaine treatment blocked the increase in receptor density. The results indicated that neonatal coca ine exposure was associated with altered responses to NMDA, stress toleranc e and pain sensitivity. Moreover, the pretreatment with NMDA receptor antag onist, MK-801, abolished or attenuated these cocaine-induced neurobehaviora l changes. (C) 2001 Elsevier Science Inc. All rights reserved.