alpha-Methyldopa metabolism in central serotonergic nerve terminals: effects on serotonin levels, synthesis and...

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.