The regulation of dopamine release from striatum slices by tetrahydrobiopterin and l -arginine-derived nitric oxide

The regulation of dopamine release by 6( R )-tetrahydrobiopterin (BH 4 ) and l -arginine-derived nitric oxide was examined by using a method of superfusion of rat striatum slices in vitro. l -Arginine, which can produce nitric oxide (NO) through the action of NO synthase, induces a concentration-dependent increase of [ 3H ] dopamine release in the superfusate of striatum slices. Pretreatment with inhibitors of NO synthase or with inhibitors of BH 4 synthesis diminishes the increase of [ 3H ] dopamine release mediated by arginine. This increase is almost completely restored following repletion of intracellular BH 4 levels by incubation of the slices with 7,8-dihydrobiopterin. Adding exogenous BH 4 directly to the superfusion fluid leads to a massive increase in [ 3H ] dopamine release which can be inhibited 75% by superoxide dismutase and catalase, but is not inhibited by N G -nitro-arginine, a NO synthase inhibitor, or alpha-methyl- p -tyrosine, a tyrosine hydroxylase inhibitor. The increase of intracellular BH 4 concentration by dihydrobiopterin administration causes a small increase of dopamine release which can be partially diminished by N G -nitro-arginine or alpha-methyl- p -tyrosine. It is suggested that the increase of dopamine release stimulated by an enhancement of intracellular BH 4 is dependent on its cofactor activity with NO synthase and tyrosine hydroxylase. This study has also demonstrated that BH 4 is a regulator of NO-mediated dopamine release in the striatum.