The early postnatal application of the NMDA antagonist MK–801 induces life long pathological changes in behaviour in rats

A hypofunction of the N-methyl-D-aspartate (NMDA) receptor system profoundly attenuates behaviour in humans as well as rodents. In a series of experiments we investigated behaviour and brain morphology in rats beginning at the age of 30d until the age of 180d following the peripheral administration of the NMDA antagonist MK–801 (dizocilpine) from day 6 to 21 of age. MK–801 treatment induced an increase of NMDA receptor protein starting around the age of 90d within the CNS. In the Elevated Plus Maze, MK–801 application profoundly reduced total distance moved, mean velocity and the time of movement in adult animals indicating a profound decrease in spontaneous activity. In the Open Field Maze the MK–801 application also reduced locomotor activity in mature rats and increased explorative behaviour in immature rats. Although memory performance in the Novel Object Recognition Memory Test was not affected per se, our results point to an increasing deficit in concentrativeness and motivation within adult but not young animals of the MK–801 treated group. Surprisingly, for almost all behavioral parameters, MK–801 treatment extinguished age-related differences occurring in the control animals. Hence, the early postnatal application of the NMDA receptor antagonist MK–801 seems to induce a series of life long lasting symptoms closely related to those occurring in schizophrenic patients which may be closely related to the pathological changes in NMDA receptor expression.