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Characterization of a Dopamine‐Releasing Action of 6 R ‐ l ‐ erythro ‐Tetrahydrobiopterin: Comparison with a 6 S ‐Form
Author(s) -
Koshimura Kunio,
Takagi Yasutaka,
Miwa Soichi,
Kido Tsuneo,
Watanabe Yasuyoshi,
Murakami Yoshio,
Kato Yuzuru,
Masaki Tomoh
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.65020827.x
Subject(s) - tetrahydrobiopterin , dopamine , tyrosine hydroxylase , microdialysis , chemistry , monoamine neurotransmitter , aromatic l amino acid decarboxylase , tyrosine , endocrinology , medicine , nitric oxide synthase , neurotransmitter , biochemistry , serotonin , biology , enzyme , receptor
6 R ‐ l ‐ erythro ‐Tetrahydrobiopterin (6 R ‐BH 4 ) is a cofactor for aromatic l ‐amino acid hydroxylases and nitric oxide synthase. Recently, we have reported that independently of its cofactor activities, 6 R ‐BH 4 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 6 S ‐BH 4 , a diastereoisomer of 6 R ‐BH 4 , on dopamine release in the rat striatum by using brain microdialysis and compared its effects with those of 6 R ‐BH 4 . Perfusion of 6 S ‐BH 4 or 6 R ‐BH 4 through the dialysis probe increased extracellular dopamine levels (an index of in vivo dopamine release) concentration dependently; the maximal increase by 6 S ‐BH 4 , was one‐sixth of that by 6 R ‐BH 4 . 6 S ‐BH 4 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 6 R ‐BH 4 . The increase in the DOPA levels induced by either of the pteridines was abolished after pretreatment of rats with α‐methyl‐ p ‐tyrosine (an inhibitor of tyrosine hydroxylase). Under the same conditions, the 6 S ‐BH 4 ‐induced dopamine release was abolished, but most of the 6 R ‐BH 4 ‐induced increase persisted. Coadministration of 6 S ‐BH 4 with 6 R ‐BH 4 inhibited the increase in dopamine release induced by 6 R ‐BH 4 alone. These results show that 6 R ‐BH 4 stimulates dopamine release by acting at the specific recognition site on the neuronal membrane, and that 6 S ‐BH 4 acts as an antagonist of 6 R ‐BH 4 at this site, although it has cofactor activities.