Enhancement of acetylcholine release in the hippocampus by 6 R- L-erythro -5,6,7,8-tetrahydrobiopterin is mediated by 5-hydroxytryptamine

Abstract

Recently, we reported that 6 R- l-erythro-tetrahydrobiopterin (6 R-BH 4), a natural cofactor for l-aromatic amino acid hydroxylases, enhances in vivo release of acetylcholine (ACh) in the rat hippocampus: the enhancement was abolished after depletion of brain catecholamines and 5-hydroxytryptamine (5-HT) by pretreatment with reserpine. In the present study, we have used in vivo brain microdialysis to clarify the neuronal mechanism involved in the enhancement of ACh release by 6 R-BH 4. After depletion of catecholamines by pretreatment of rats with α-methyl- p-tyrosine, 6 R-BH 4 added to the perfusion fluidstill induced an incrase in extracellular ACh levels monitored by microdialysis as an index of ACh release. In contrast, after depletion of 5-HT by pretreatment with p-chlorophenylalanine, most of the 6R-BH 4- iduced enhancement was eliminated. Exogenous 5-HT and dopamine (DA) but not noradrenaline aded to the perfusion fluid stimulated ACh release with 5-HT being far more potent. Intraperitonel administration of 5-hydroxytryptophan and l-DOPA also enhanced ACh releas, presumably by their conversion to 5-HT and catecholamines, respectively. Administration of 6 R0BH 4 increased hippocampal 5-HT release, as indicated by increase extracellular levels of the major 5-HT metabolite, 5-hydroxyindoleacetic acid. These results suggest that 6 R-BH 4 stimulates ACh release in the hippocampus, mainly by augmenting release of 5-HT, a potent stimulator of ACh release, and partly by augmenting release of DA.