6R-L-erythro-5,6,7,8-tetrahydrobiopterin as a regulator of dopamine and serotonin biosynthesis in the rat brain.
6R-L-Erythro-tetrahydrobiopterin (6R-BH4), the natural isomer of tetrahydrobiopterin, was synthesized from 7,8-dihydrobiopterin using dihydrofolate reductase. The effects of intracerebroventricular injection of 6R-BH4 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-BH4, and reached a plateau when the dose was more than 300 micrograms/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-BH4 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-BH4. These results suggest that 6R-BH4 concentration may be submaximal within DA and 5-HT neurons, and that an increase in 6R-BH4 in the brain enhances the biosyntheses of DA and 5-HT.
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis*; D006900:Hydroxylation; D007536:Isomerism; D011339:Probenecid / Q000494:pharmacology; D011621:Pteridines / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000096:biosynthesis*; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D011621:Pteridines; D001708:Biopterins; D012701:Serotonin; D014443:Tyrosine; D014364:Tryptophan; C003402:sapropterin; D011339:Probenecid; D004298:Dopamine