Comparative effects of various serotonin releasing agents in mice

Five serotonin (5-HT) releasers, p-chlorophenylethylamine (p-Cl-PEA), p-methoxyphenyl-ethylamine (p-CH₃O-PEA), 4-methyl-alpha-ethyl-meta-tyramine (H75/12), fenfluramine and p-chloro-amphetamine (p-CA) were compared as to their effects on mouse brain 5-HT metabolism. All 5-HT releasers had similar ed₅₀ values (0.34–0.70 μM) for tritiated 5-HT ([³H]5-HT) release from brain synaptosomes. With the exception of H75/12, they had similar potencies for the production of the ‘serotonin syndrome,’ which probably reflect their in vivo 5-HT releasing actions. H75/12 was also the only 5-HT releaser that did not elevate brain tryptophan concentration. p-CH₃-PEA and H75/12 did not have any long-term effects on brain 5-HT, 5-hydroxyindoleacetic acid (5-H1AA), or tryptophan hydroxylase activity, in contrast to the reported neurotoxic effects of p-CA and fenfluramine. p-Cl-PEA and p-CH₃O-PEA were the only 5-HT releasers that increased brain 5-HT and 5-HIAA levels. Despite the structural similarities of these five 5-HT releasers, we have found considerable differences in their actions on brain 5-HT metabolism.