Structural, neurochemical and behavioural consequences of neonatal blockade of NMDA receptor through chronic treatment with CGP 39551 or MK-801.

Recent evidence suggests that NMDA receptors may be involved in survival of neurons and establishment of correct connectivity during development. We have treated rat pups from postnatal day 1 to 22 with daily s.c. injections of a competitive (CGP 39551) and a non-competitive (MK-801) antagonist of the NMDA receptor. Body weight of treated rats was decreased by 50-65% at postnatal day 24 and by 25-32% at 70 days of age. Brain weight was decreased by 16-24% at both ages. Among the different brain regions, the cerebellum and striatum appeared more decreased in size than the cortex and hippocampus. Only few minor, and in some cases transient, differences were measured in the cerebellum, the hippocampus and the cortex for a battery of neurochemical markers related to cholinergic, GABAergic and glutamatergic transmission as well as to astrocyte and oligodendrocyte activity. When tested in actometric cages from postnatal days 28 to 60, treated rats exhibited a dramatic increase of spontaneous locomotor activity which was maximal in 28-day-old animals (380% and 250% of control values in CGP 39551 and MK-801 groups, respectively) and was still significant at 60 days of age. Therefore, long-lasting alteration of motor behaviour is obtained by the schedule of chronic treatment adopted for the present experiments. Our results suggest that blockade of NMDA receptors during the critical period of brain maturation may result in permanent alteration of neural circuits.