alpha-Methyldopa metabolism in central serotonergic nerve terminals: effects on serotonin levels, synthesis and release.
The direct effects of in vivo methyldopa administration on serotonin (5-HT) neurochemistry was investigated. Specifically the ability of methyldopa to alter nerve terminal-associated 5-HT synthesis, storage and release and the possibility that 5-HT nerve terminals accumulate methyldopamine (the product of decarboxylation of methyldopa) was investigated. Synaptosomes isolated from rats given 200 mg/kg of methyldopa (calculated as the free amino acid) 2 h prior to killing exhibited a 25% reduction in intrasynaptosomal 5-HT and a 15% reduction in 5-HT synthesis when compared to synaptosomes from saline-treated animals. In addition a 15% reduction in synaptosomal tryptophan levels was observed. Despite these changes there was no apparent decrease in basal or depolarization-induced 5-HT release from synaptosomes of methyldopa-treated rats. The presence of methyldopamine within 5-HT-containing synaptosomes was confirmed by demonstrating that p-chloroamphetamine, a selective 5-HT releasing agent, could release both methyldopamine and 5-HT from synaptosomes and that this release could be selectively antagonised by fluoxetine, a selective 5-HT uptake inhibitor. The significance of these data with respect to the involvement of 5-HT neurons in the hypotensive action of methyldopa is discussed.
Wolf
W A
WA
Baker Medical Research Institute, Prahran, Victoria, Australia.
Bobik
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008750:Methyldopa / Q000378:metabolism*; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002395:Catecholamines; D002396:Catechols; D007211:Indoles; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008750:Methyldopa