The Effects of 5‐hydroxytryptophan and 5‐hydroxytryptamine on Dopamine Synthesis and Release in Rat Brain Striatal Synaptosomes¹

The effects of 5‐hydroxytryptophan (5‐HTP) and serotonin (5‐HT) on dopamine synthesis and release in rat brain striatal synaptosomes have been examined and compared to the effects of tyramine and dopamine. Serotonin inhibited dopamine synthesis from tyrosine, with 25% inhibition occurring at 3 μM‐5‐HT and 60% inhibition at 200 μM. Dopamine synthesis from DOPA was also inhibited by 5‐HT, with 30% inhibition occurring at 200 μ. At 200 μM‐5‐HTP, dopamine synthesis from both tyrosine and DOPA was inhibited about 70%. When just the tyrosine hydroxylation step was measured in the intact synaptosome, 5‐HT, 5‐HTP, tyramine and dopamine all caused significant inhibition, but only dopamine inhibited soluble tyrosine hydroxylase [L‐tyrosine 3‐monooxygenase; L‐tyrosine, tetrahydropteridine oxygen oxidoreductase (3‐hydroxylating); EC 1.14.16.2] prepared from lysed synaptosomes. Particulate tyrosine hydroxylase was not inhibited by 10 μM‐5‐HT, but was about 20% inhibited by 200 μM‐5‐HT and 5‐HTP. At 200 μM both 5‐HT and 5‐HTP stimulated endogenous dopamine release. These experiments suggest that exposure of dopaminergic neurons to 5‐HT or 5‐HTP leads to an inhibition of dopamine synthesis, mediated in part by an intraneuronal displacement of dopamine from vesicle storage sites, leading to an increase in dopamine‐induced feedback inhibition of tyrosine hydroxylase, and in part by a direct inhibition of DOPA decarboxylation.