Long-lasting effects of chronic neonatal blockade of N-methyl-D-aspartate receptor through the competitive antagonist CGP 39551 in rats.

A competitive antagonist of the N-methyl-D-aspartate receptor, CGP 39551, was administered daily to neonatal rats with increasing doses from postnatal day 1 to 22. These animals displayed approximately 50% decrease of body weight at the end of treatment and, therefore, both normal and neonatally undernourished rats were used as controls. At a young adult stage (55-75 days of age) CGP 39551-treated rats showed a much higher spontaneous locomotor activity as compared to control groups. This hypermotility was counteracted by D1 and D2 dopamine antagonists while administration of methamphetamine increased, to the same extent, the differential basal locomotor activity of treated and control groups. The locomotor activity response to the N-methyl-D-aspartate channel blocker, dizocilpine maleate, was significantly shifted to the right for treated rats so that an equivalent increase of motility was obtained by doubling the dose effective for control animals. In in vivo microdialysis experiments, similar amounts of dopamine were collected from the striatum of treated and control rats after high K+ or methamphetamine stimulation, the only difference being a greater Ca2+ dependency of the depolarization-induced dopamine release in treated rats. Assays for different neurochemical parameters, carried out at 80-90 days of age, suggested some alteration of the balance between excitatory and inhibitory circuits in the basal ganglia of CGP 39551-treated rats. Tyrosine hydroxylase and calbindin immunostaining, as well as acetylcholinesterase histochemistry, revealed a similar picture in the striatum of treated and control rats. However, 5'-nucleotidase histochemistry showed a stronger and evenly distributed reactivity in the striatum of treated rats, opposite to the weaker and patchy localization of normal or undernourished controls. From the present results it is possible to conclude that chronic blockade of the N-methyl-D-aspartate receptor during neonatal brain maturation results in long-lasting alteration of locomotor activity which appears related to functional changes of the dopamine receptors as well as to an altered balance between various excitatory and inhibitory neurotransmitter and neuromodulatory systems.