STRUCTURAL, NEUROCHEMICAL AND BEHAVIORAL 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 surviv al of neurons and establishment of correct connectivity during develop ment. 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 ag e. Brain weight was decreased by 16-24% at both ages. Among the differ ent 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 hipp ocampus 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 cag es from postnatal days 28 to 60, treated rats exhibited a dramatic inc rease of spontaneous locomotor activity which was maximal in 28-day-ol d animals (380% and 250% of control values in CGP 39551 and MK-801 gro ups, respectively) and was still significant at 60 days of age. Theref ore, long-lasting alteration of motor behaviour is obtained by the sch edule of chronic treatment adopted for the present experiments. Our re sults suggest that blockade of NMDA receptors during the critical peri od of brain maturation may result in permanent alteration of neural ci rcuits.