CHRONIC NEONATAL BLOCKADE OF N-METHYL-D-ASPARTATE RECEPTOR BY CGP-39551 INCREASES DOPAMINERGIC FUNCTION IN ADULT-RAT

Following chronic neonatal treatment with the competitive N-methyl-D-aspartate antagonist CGP 39551, adult rats showed increased behavioral responses to the D-2 dopamine receptor stimulation. In nucleus accumbens and in n. striatum of similarly treated rats increases in D-2 dopamine receptor number were observed. CGP 39551 was administered daily to neonatal rats with increasing doses from postnatal day 1 to 22. At postnatal days 70-82, the rats were observed for hyperactivity induced by the selective D-2 dopamine receptor agonist LY 171555, the grooming behavior elicited by the specific D-1 dopamine receptor stimulating agent SKF 38393 and the stereotypies induced by the mixed D-1/D-2 receptor agonist apomorphine. [H-3]Spiroperidol and [H-3]SCH 23390 specific binding to membranes of nucleus accumbens, nucleus striatum and frontal cortex of similarly treated rats was measured. The hypermotility and the stereotyped behavior induced by LY 171555 and apomorphine, respectively, were augmented, whereas grooming behavior elicited by SKF 38393 was unaffected, in CGP 39551-treated rats. Consistently, both in nucleus accumbens and in n. striatum an increase in [H-3]Spiroperidol specific binding was observed, while [H-3]SCH 23390 specific binding did not change. The study demonstrates that chronic blockade of N-methyl-D-aspartate receptor during the critical period of brain maturation results in long-lasting dopaminergic functional changes.