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 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.
Koshimura
K
K
Department of Medicine, Shimane Medical University, Izumo, Japan.
Takagi
Y
Y
Miwa
S
S
Kido
T
T
Watanabe
Y
Y
Murakami
Y
Y
Kato
Y
Y
Masaki
T
T
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001708:Biopterins; D004295:Dihydroxyphenylalanine; D014446:Tyrosine 3-Monooxygenase; C003402:sapropterin; D004298:Dopamine