6 R- l-Erythro-5,6,7,8-tetrahydrobiopterin as a regulator of dopamine and serotonin biosynthesis in the rat brain

Abstract

6 R- l-Erythro-tetrahydrobiopterin (6R-BH 4), the natural isomer of tetrahydrobiopterin, was synthesized from 7,8-dihydrobiopterin using dihydrofolate reductase. The effects of intracerebroventricular injection of 6R-BH 4 on the biosyntheses of neurotransmitter monoamines in the rat brain were investigated by measuring accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after the inhibition of aromatic l-amino acid decarboxylase by NSD 1015 and the contents of metabolites of dopamine (DA) and 5-hydroxytryptamine (5-HT). The formation of DOPA and 5-HTP increased after the injection, reached a maximum level at about 1 h, then leveled off and reached a plateau over 2 h up to 8 h. The formation of DOPA and 5-HTP increased dose-dependently in the whole brain after the injection of 6R-BH 4, and reached a plateau when the dose was more than 300 μg/rat. The enhancement was 100 and 70% for DOPA and 5-HTP, respectively. The formation of DOPA and 5-HTP increased in four brain regions, but the degree of stimulation was different among the brain regions. The contents of DA and 5-HT metabolites increased after the injection of 6R-BH 4 in all brain regions tested, especially in the diencephalon and brain stem. The contents of DA and 5-HT increased slightly after the injection of 6R-BH 4. These results suggest that 6R-BH 4 concentration may be submaximal within DA and 5-HT neurons, and that an increase in 6R-BH 4 in the brain enhances the biosyntheses of DA and 5-HT.