CHARACTERIZATION OF A DOPAMINE-RELEASING ACTION OF 6R-L-ERYTHRO-TETRAHYDROBIOPTERIN - COMPARISON WITH A 6S-FORM

6R-L-erythro-Tetrahydrobiopterin (6R-BH4) is a cofactor for aromatic L -amino acid hydroxylases and nitric oxide synthase. Recently, we have reported that independently of its cofactor activities, 6R-BH4 acts fr om the outside of neurons in the brain to enhance the release of monoa mine neurotransmitters such as dopamine, To characterize the pharmacol ogical properties of the action, we examined the effects of 6S-BH4, a diastereoisomer of 6R-BH4, on dopamine release in the rat striatum by using brain microdialysis and compared its effects with those of 6R-BH 4. Perfusion of 6S-BH4 or 6R-BH4 through the dialysis probe increased extracellular dopamine levels (an index of in vivo dopamine release) c oncentration dependently; the maximal increase by 6S-BH4, was one-sixt h of that by 6R-BH4, 6S-BH4 increased extracellular DOPA levels in the presence of NSD 1015, an inhibitor of aromatic L-amino acid decarboxy lase (an index of in vivo tyrosine hydroxylase activity), to an extent similar to the increase induced by 6R-BH4, The increase in the DOPA l evels induced by either of the pteridines was abolished after pretreat ment of rats with alpha-methyl-p-tyrosine (an inhibitor of tyrosine hy droxylase). Under the same conditions, the 6S-BH4-induced dopamine rel ease was abolished, but most of the 6R-BH4-induced increase persisted. Coadministration of 6S-BH4 with 6R-BH4 inhibited the increase in dopa mine release induced by 6R-BH4 alone. These results show that 6R-BH4 s timulates dopamine release by acting at the specific recognition site on the neuronal membrane, and that 6S-BH4 acts as an antagonist of 6R- BH4 at this site, although it has cofactor activities.