Enhancement of acetylcholine release in the hippocampus by 6R-L-erythro-5,6,7,8-tetrahydrobiopterin is mediated by 5-hydroxytryptamine.
Recently, we reported that 6R-L-erythro-tetrahydrobiopterin (6R-BH4), 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 6R-BH4. After depletion of catecholamines by pretreatment of rats with alpha-methyl-p-tyrosine, 6R-BH4 added to the perfusion fluid still induced an increase 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-BH4-induced enhancement was eliminated. Exogenous 5-HT and dopamine (DA) but not noradrenaline added to the perfusion fluid stimulated ACh release with 5-HT being far more potent. Intraperitoneal administration of 5-hydroxytryptophan and L-DOPA also enhanced ACh release, presumably by their conversion to 5-HT and catecholamines, respectively. Administration of 6R-BH4 increased hippocampal 5-HT release, as indicated by increased extracellular levels of the major 5-HT metabolite, 5-hydroxyindoleacetic acid. These results suggest that 6R-BH4 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.
Ohue
T
T
Department of Pharmacology, Kyoto University, Faculty of Medicine, Japan.
Koshimura
K
K
Takagi
Y
Y
Watanabe
Y
Y
Miwa
S
S
Masaki
T
T
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000109:Acetylcholine / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D010134:Fenclonine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007980:Levodopa / Q000378:metabolism; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
D015306:Biogenic Monoamines; D008781:Methyltyrosines; D001708:Biopterins; D012701:Serotonin; D007980:Levodopa; D019805:alpha-Methyltyrosine; D006916:5-Hydroxytryptophan; D014446:Tyrosine 3-Monooxygenase; C003402:sapropterin; D000109:Acetylcholine; D010134:Fenclonine