Dopamine-Releasing Action of 6R-l-erythro-Tetrahydrobiopterin: Analysis of Its Action Site Using Sepiapterin
Article first published online: 23 NOV 2002
Journal of Neurochemistry
Volume 63, Issue 2, pages 649–654, August 1994
How to Cite
Koshimura, K., Miwa, S. and Watanabe, Y. (1994), Dopamine-Releasing Action of 6R-l-erythro-Tetrahydrobiopterin: Analysis of Its Action Site Using Sepiapterin. Journal of Neurochemistry, 63: 649–654. doi: 10.1046/j.1471-4159.1994.63020649.x
- Issue published online: 23 NOV 2002
- Article first published online: 23 NOV 2002
- Received September 16, 1993; revised manuscript received December 6, 1993; accepted December 6, 1993.
- Nitric oxide synthase;
- Dopamine release;
- Brain microdialysis;
Abstract: Recently, we reported that 6R-l-erythro-tetrahydrobiopterin (6R-BH4), a natural cofactor for hydroxylases of tyrosine and tryptophan, has a monoamine-releasing action independent of its cofactor activity. Here we attempted to determine whether 6R-BH4 acts inside the cell or from the outside of the cell by using brain microdialysis in the rat striatum. For this purpose, sepiapterin, an immediate precursor of 6R-BH4 in the salvage pathway, was used to selectively increase the intracellular 6R-BH4 levels. Dialytic perfusion of sepiapterin increased tissue levels of reduced biopterin (mainly 6R-BH4) but not the extracellular levels. Administration of sepiapterin increased the extracellular levels of 3,4-dihydroxyphenylalanine (DOPA) (an index of in vivo tyrosine hydroxylase activity) and of dopamine (DA) (an index of in vivo DA release). Either of the increases was eliminated after pretreatment with a tyrosine hydroxylase inhibitor α-methyl-p-tyrosine. Administration of 6R-BH4 increased extracellular levels of reduced biopterin, DOPA, and DA. After pretreatment with α-methyl-p-tyrosine, the increase in DOPA levels was abolished, but most of the increase in DA levels persisted. The increase in DA levels also persisted after pretreatment with nitric oxide synthase inhibitors. These data demonstrate that 6R-BH4 stimulates DA release directly, independent of its cofactor action for tyrosine hydroxylase and nitric oxide synthase, by acting from the outside of neurons.