To clarify the therapeutic effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) on the abnormal behaviors induced by neonatal 5,7-dihydroxytryptamine (5,7-DHT, 100 mug; i.c.v.) treatment in immature rats, 6R-BH4 (10-40 mg/kg) was administered intraperitoneally from 22nd to 28th days or only once on the 28th day. The locomotion activities decreased dramatically in 5,7-DHT-treated rats (p < 0.01; as compared to controls) on the 28th day. The reduced locomotion was recovered dose-dependently by repeated administration of 6R-BH4, whereas it was not altered after a single injection of 6R-BH4. In addition, repeated administration of 6R-BH4 significantly facilitated 5-HT turnover ratio (5-HIAA/5-HT) in the striatum, cerebral cortex, and cerebellum. These findings suggest that the behavioral restoration by 6R-BH4 might be due to the enhancement of 5-HT turnover by accumulated but not a single dose of 6R-BH4. (C) 2003 Elsevier Science (USA). All rights reserved.