6R-L-erythro-5,6,7,8-Tetrahydrobiopterin and Dopamine Release

Abstract

SummaryWe previously reported that intracerebroventricular administration of 6,7,, a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase, induces an increase in DOPA levels (as an index of DA biosynthesis) and in levels of DA metabolites (as an index of DA release) in the rat brain: the increase in DOPA levels was larger than that of DA metabolites, indicating that 6R-BH 4 enhances DA release. In the present study, we examined the effects of 6R-BH 4 on DA release in vivo from the striatum of male Wistar rats and its mechanism of action using brain microdialysis. When various concentrations of 6R-BJL, 6S-BJL (a diastereoisomer of 6R-BH 4 ) or 6-methyltetrahydropterin (6-MPJL) were added to the perfusion fluid of microdialysis probes, DA levels collected in dialysates increased in a concentration-dependent manner: the 6R-BJL-induced increase was far greater than the increase induced by 6S-BH4 or 6-MPJL. Biopterin had little effect on the DA levels. After i.p. injection of250 mg/kg ofa-methyl-p-tyrosine (a-MT; an inhibitor of tyrosine hydroxylase), most of the 6R-BH 4 -induced increase persisted but the increase induced by 6S-BJL or 6-MPH4 was abolished. The 6R-BH4 -induced increase in DA levels in dialysates was abolished after addition of tetrodotoxin (50 J.1M) to the perfusion fluid, but it persisted after i.p. injection of 100 mg/kg of nomifensine which completely inhibited DA reuptake. The increase in DA levels also persisted after administration of nitric oxide synthase inhibitors. The 6R-BJL-induced increase in DA levels was inhibited by co-administration of 6S-BJL or 6-MPJL. Administration of sepiapterin (an immediate precursor of 6R-BJL) increased tissue levels of reduced biopterin (mainly consisting of 6R-BJL) but not its extracellular levels monitored by brain microdialysis, indicating that it selectively increases the intracellular 6R-BJL levels. In contrast, administration of 6R-BH 4 increased both tissue levels of reduced biopterin and its extracellular levels, indicating that it increases both the intraand extra-cellular 6R-BH 4 leveles. DA levels in dialysates was elevated following administration of sepiaterin (an immediate precursor of 6R-BJL), but the elevation was abolished after pretreatment with a-MT. Furthermore, 6R-BJL increased firing rates of neurons in the dorsal motor nucleus of vagus monitored by a slice patch method. These results suggest that 6R-BJL has a DA releasing action independent of its cofactor for tyrosine hydroxylase and nitric oxide synthase, which is mediated by a specific recognition site for 6R-BH4 on DA neurons or related cells.

Evidence for a Tetrahydrobiopterin Deficit in Schizophrenia

“…Following administration of BH 4 in vivo rat microdialysis studies have shown that (a) DA release was increased in the striatum with the release not dependent on the biosynthesis of DA [9,13] , and (b) the DA-releasing action was independent of the action of BH 4 as a cofactor for TH and NOS, and was mediated by a specifi c recognition site for BH 4 on DA neurons or related cells [14] . In addition, dialytic perfusion of BH 4 in rats was determined via microdialysis to increase the in vivo release of DA (in the striatum and frontal cortex), 5-HT (in the striatum), and glutamate (in striatum and frontal cortex) [10] .…”