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

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 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 alpha-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.

Neuropsychotoxicity of Abused Drugs: Molecular and Neural Mechanisms of Neuropsychotoxicity Induced by Methamphetamine, 3,4-Methylenedioxymethamphetamine (Ecstasy), and 5-Methoxy-N,N-diisopropyltryptamine (Foxy)

“…The lack of serotonergic neurotoxicity by METH and MDMA in this study may be due to lack of a sufficient number of dopaminergic neurons or little interaction between dopaminergic and serotonergic neurons in the mesencephalic slice culture. Consistently, it was reported that systemic injection of MDMA produced serotonergic neurotoxicity, while local injection of MDMA into the brain had no effect (33). On the other hand, sustained exposure to 5-MeO-DiPT dramatically decreased the intracellular 5-HT tissue contents and […”

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

“…The L-DOPA formed through this pathway can then be converted to DA via aromatic amino acid decarboxylase in 5-HT neurons. This aberrant formation of DA within presumably 5-HT neurons may not only contribute to MDMA-induced DA release in the DA-sparse hippocampus but also may contribute to DA-derived oxidative damage to 5-HT terminals (Breier et al, 2006).…”

“…An additional mechanism by which high doses of MDMA may increase extracellular concentrations of DA in the hippocampus is through an increase in brain tyrosine (Breier et al, 2006). However, the increase in DA produced by elevations in tyrosine does not appear to be through activation of tyrosine hydroxylase but rather through the non-enzymatic hydroxylation of tyrosine to DOPA caused by the increase in hydroxyl radicals following administration of MDMA (Shankaran et al, 1999a, b;Colado et al, 1997).…”

Comparative potencies of 3,4‐methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5‐HT transport in mammalian cell lines

“…In light of the central role of monoamine transporters in mediating the pharmacological actions of MDMA, it was decided to investigate the effects of the MDMA analogues on NET and SERT transport in vitro, using two separate mammalian cell lines. Although the significance of DAT in mediating both the physiological and potentially toxicological effects of MDMA should not be underestimated (Colado et al, 2004;Breier et al, 2006;Rothman and Baumann, 2006), MDMA has typically demonstrated a greater inhibitory potency at NET and SERT compared to DAT in vitro (Rothman and Baumann, 2003;Pifl et al, 2005;Verrico et al, 2005). Consequently, it was decided to perform this investigation using NET and SERT.…”