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 from the outside of 
neurons in the brain to enhance the release of monoamine neurotransmitters such 
as dopamine. To characterize the pharmacological 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-BH4. Perfusion of 6S-BH4 or 6R-BH4 through the dialysis probe 
increased extracellular dopamine levels (an index of in vivo dopamine release) 
concentration dependently; the maximal increase by 6S-BH4, was one-sixth of that 
by 6R-BH4. 6S-BH4 increased extracellular DOPA levels in the presence of NSD 
1015, an inhibitor of aromatic L-amino acid decarboxylase (an index of in vivo 
tyrosine hydroxylase activity), to an extent similar to the increase induced by 
6R-BH4. The increase in the DOPA levels induced by either of the pteridines was 
abolished after pretreatment of rats with alpha-methyl-p-tyrosine (an inhibitor 
of tyrosine hydroxylase). Under the same conditions, the 6S-BH4-induced dopamine 
release was abolished, but most of the 6R-BH4-induced increase persisted. 
Coadministration of 6S-BH4 with 6R-BH4 inhibited the increase in dopamine 
release induced by 6R-BH4 alone. These results show that 6R-BH4 stimulates 
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.