L-Tyrosine Contributes to (+)-3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletions
Joseph M. Breier, Michael G. Bankson, Bryan K. Yamamoto
Journal of Neuroscience January 4, 2006 DOI: 10.1523/jneurosci.3353-05.2006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats (implied, not explicitly stated) |
| Interventions | MDMA l-tyrosine |
| Dose | neurotoxic doses of MDMA (exact dose not specified) |
| Topics | MDMA Serotonin |
| Key findings | MDMA increases brain tyrosine, which is nonenzymatically converted to DOPA and then dopamine via AADC, leading to long-term serotonin depletion. Local tyrosine infusion potentiated dopamine increases and serotonin depletion, while AADC inhibition attenuated these effects. |
Abstract
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 vitroresults show thatl-tyrosine can be hydroxylated nonenzymatically to the DA precursorl-3,4-dihydroxyphenylalanine (DOPA) under pro-oxidant conditions. The local infusion ofl-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) inhibitorm-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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- Neuropsychotoxicity of abused drugs: molecular and neural mechanisms of neuropsychotoxicity induced by methamphetamine, 3,4-methylenedioxymethamphetamine (ecstasy), and 5-methoxy-N,N-diisopropyltryptamine (foxy). Journal of Pharmacological Sciences 2008
- Comparative potencies of 3,4‐methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5‐HT transport in mammalian cell lines British Journal of Pharmacology September 24, 2007
- Gut Microbiota-Mediated Amino Acid Reprogramming in Ketamine-Induced Neurotoxicity: A Novel Microbiota-Amino Acid-Mitochondrial Axis Associated with Cognitive Deficits. Neuropharmacology October 27, 2025
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Cites 17
- 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Journal of Pharmacology and Experimental Therapeutics September 1, 1987
- In vivo evidence for free radical involvement in the degeneration of rat brain 5‐HT following administration of MDMA (‘ecstasy’) and p‐chloroamphetamine but not the degeneration following fenfluramine British Journal of Pharmacology July 1, 1997
- Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (+/-)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response. Journal of Pharmacology and Experimental Therapeutics October 1, 1995
- In vivo detection of short- and long-term MDMA neurotoxicity?a positron emission tomography study in the living baboon brain Synapse June 1, 1998
- Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4‐methylenedioxymethamphetamine): Assessment using quantitative autoradiography Synapse August 1, 1991
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