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L-Tyrosine Contributes to (+)-3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletions

2006; Society for Neuroscience; Volume: 26; Issue: 1 Linguagem: Inglês

10.1523/jneurosci.3353-05.2006

1529-2401

Joseph M. Breier, Michael G. Bankson, Bryan K. Yamamoto,

Psychedelics and Drug Studies

The specific mechanisms underlying (+)-3,4-methylenedioxymethamphetamine (MDMA)-induced damage to 5-HT terminals are unknown. Despite the hypothesized role for dopamine (DA) and DA-derived free radicals in mediating this damage, it remains unclear why MDMA produces long-term depletions of 5-HT in brain regions that are sparsely innervated by DA neurons. We hypothesized that the precursor to DA biosynthesis, tyrosine, mediates MDMA-induced 5-HT depletions. Extracellular tyrosine concentrations increased fivefold in striatum and 2.5-fold in hippocampus during the administration of neurotoxic doses of MDMA. In vitro results show that l -tyrosine can be hydroxylated nonenzymatically to the DA precursor l -3,4-dihydroxyphenylalanine (DOPA) under pro-oxidant conditions. The local infusion of l -tyrosine into the striatum or hippocampus during MDMA administration potentiated the acute increase in extracellular DA and the long-term depletion of 5-HT after MDMA. Coinfusion of the aromatic amino acid decarboxylase (AADC) inhibitor m -hydroxybenzylhydrazine attenuated these effects in hippocampus and decreased basal extracellular DA in the striatum. In contrast, the reverse dialysis of the tyrosine hydroxylase inhibitor α-methyl- p -tyrosine into the hippocampus did not affect MDMA-induced increases in extracellular DA or the long-term depletion in 5-HT. These results show that MDMA increases the concentration of tyrosine in the brain to cause a long-term depletion of 5-HT via the nonenzymatic, tyrosine hydroxylase-independent, hydroxylation of tyrosine to DOPA and subsequently to DA via AADC. Overall, the findings suggest that MDMA depletes 5-HT by increasing tyrosine and its eventual conversion to DA within 5-HT terminals.