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

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‐BH₄did not alter the spontaneous release of [³H]serotonin but it did significantly increase release when slices were depolarized with 30 mM KC1. 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 isotner 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 KC1‐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.