Neurobehavioral profile of subcutaneously administered MK-801 in the rat

MK-801 (dizocilpine) is an NMDA antagonist known to cause vacuolization and necrosis in susceptible cortical neurons. The objectives of the present work were to characterize the behavioral effects produced by a single administration of MK-801 and to determine how these effects may relate to the morphological changes seen in the central nervous system. Female rats (8/ group), approximately 9 weeks of age, received one of three doses of (+)MK-801 (0.1, 0.25, and 0.5 mg/kg) subcutaneously. Behavioral evaluation, using detailed clinical observations or a functional observational battery, was conducted every 15 minutes from 15-120 minutes post dosing and on Days 2, 3 and 7. Locomotor activity was assessed on Days 1,3,7 and 14. Stereotypy and ataxia were seen in all MK-801 groups soon after dosing, and continued to be observed in the two lower dose groups out to 2 hours. By 45 minutes post dosing, most of the rats from the 0.5 mg/kg group were completely immobile and did not show recovery for several hours. At 24 hours post dosing when all animals from the 0.5 mg/kg group were mobile, stereotypy and ataxia were evident. A differential dose effect was observed on locomotor activity on Day 1. Markedly increased locomotor activity was seen in the 0.1 mg/kg group, whereas activity was decreased in the 0.5 mg/kg group. This decrease at the highest dose level continued to be seen up to 3 days post dosing. In conclusion, acute dosing with MK-801 produced a behavioral pattern that was markedly affected by the increasing severity of ataxia with increasing dose and that was similar, in many aspects, to the profile that has been seen with single dose administration of phencylidine in the rat. Comparison of the temporal pattern of behavioral change (at the 0.5 mg/kg dose level) with that of necrosis development did not suggest a direct mechanistic relationship.