Effects of 1,3-bis(tetrahydro-2-furanyl)-5-fluoro-2,4-pyrimidinedione (FD 1) on the central nervous system: (2) Effects on nigro-striatal dopaminergic neurons.
A single high oral dose of 1,3-bis(tetrahydro-2-furanyl)-5-fluoro-2, 4-pyrimidinedione (FD-1) (486.0-729.0 mg/kg) followed by daily administration of lower doses of FD-1 (121.5 mg/kg) for 2-4 weeks increased the concentration of striatal dopamine (DA) in rats. The decrease in striatal DA following an injection of alpha-methyl-p-tyrosine methyl ester (alpha-MT) was lessened by a dose of FD-1 (364.8 mg/kg, p.o.) given immediately before the alpha-MT. This may indicate a decrease in striatal DA utilization by FD-1. The increase in striatal DA after FD-1 was inhibited by two antagonists of gamma-aminobutyric acid (GABA) which act on postsynaptic receptors: bicuculline (0.5-2.0 mg/kg, i.p.) and picrotoxin (2.0 mg/kg, i.p.). The increase of DA induced by the GABA transaminase inhibitor aminooxyacetic acid (AOAA) was enhanced by FD-1. These results suggest that the action of FD-1 is mediated by GABA. FD-1 probably causes inhibition of DA release from nerve terminals resulting in an accumulation of DA in the corpus striatum.
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000502:physiology*; D005472:Fluorouracil / Q000031:analogs & derivatives*; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects; D011963:Receptors, GABA-A; D013378:Substantia Nigra / Q000187:drug effects*; D005641:Tegafur / Q000031:analogs & derivatives* / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
D000625:Aminooxyacetic Acid; D000970:Antineoplastic Agents; D001640:Bicuculline; D004298:Dopamine; D005472:Fluorouracil; D008781:Methyltyrosines; D010852:Picrotoxin; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D005641:Tegafur; D014446:Tyrosine 3-Monooxygenase; D019805:alpha-Methyltyrosine; C016882:FD 1