Effect of Tetrahydrobiopterin on Serotonin Synthesis, Release, and Metabolism in Superfused Hippocampal Slices

Abstract

The effects of 6R-5,6,7,8-tetrahydro-L-biopterin (6R-BH4), the in vivo cofactor for tryptophan hydroxylase, on the synthesis, release, and metabolism of serotonin were studied in superfused slices from rat hippocampus. 6R-BH4 did not alter the spontaneous release of [3H]serotonin but it did significantly increase release when slices were depolarized with 30 mM KCl. Under the same incubation conditions, 6R-BH4 altered neither the synthesis (basal or tryptophan-stimulated) nor the metabolism of serotonin in hippocampal slices. The synthetic pteridine 6-methyl-5,6,7,8-tetrahydropterin also augmented release under depolarizing conditions whereas biopterin, the oxidized form of 6R-BH4, did not. The 6S isomer of BH4, which is relatively inactive as a cofactor for tryptophan hydroxylase, was equipotent with 6R-BH4 in stimulating serotonin release. 6R-BH4 did not inhibit serotonin uptake nor did it function as a serotonin autoreceptor antagonist to increase release. A direct serotonin releasing effect of 6R-BH4, like that produced by p-chloroamphetamine, could also be ruled out. At suboptimal concentrations of extracellular calcium, the KCl-induced release of 3H was significantly reduced, yet the increase in release caused by BH4 remained the same in magnitude. It is concluded that 6R-BH4 increases the depolarization-induced release of serotonin through an interaction with the release mechanism itself, possibly by enhancing calcium influx or by increasing the sensitivity of the release mechanism to calcium. The effects of 6R-BH4 on serotonin release are independent from its function as the cofactor for tryptophan hydroxylase.

Alterations in dopamine and glutamate neurotransmission in tetrahydrobiopterin deficient spr-/- mice: relevance to schizophrenia

“…BH4-induced release of DA was detected in rat striatum in vivo (53) as well as in striatal slices in vitro (54). Exogenous BH4 also elevated levels of 5HT in rat hippocampal slices (55) (Fig. 2).…”

The role of endogenous serotonin in methamphetamine‐induced neurotoxicity to dopamine nerve endings of the striatum

“…Insoluble protein was removed by centrifugation and DA was determined by HPLC with electrochemical detection. In order to characterize the 5HT neurochemical phenotype of TPH2−/− mice, the striatal levels of DA, 5HT and 5‐hydroxyindole acetic acid in TPH2−/− mice and wild‐type controls were determined by HPLC (Wolf et al. 1991).…”

Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach

“…Several studies, although mostly not related to PKU, suggest that BH 4 has an effect on monoaminergic neurotransmitter synthesis. in vivo microdialysis with intracerebral BH 4 infusion was found to increase neuronal dopamine and serotonin release in a dose‐dependent manner in striatum from healthy rats . For dopamine, a similar effect of BH 4 has been observed in rat frontal cortex .…”

“…57 Although controversy exists concerning the exact role of NO in monoaminergic neurotransmission, the majority of data has indicated that NO stimulates dopaminergic, noradrenergic, and serotonergic neuronal release. 57 Secondly, besides acting through NO, BH 4 has also been shown to directly enhance neuronal dopamine and serotonin release 49,50,53,58,59 independent of its cofactor activity. Such effect would be mediated by activation of Ca 2+ channels 53,58,60 via the cAMP protein kinase A pathway.…”