L-tyrosine contributes to (+)-3,4-methylenedioxymethamphetamine-induced serotonin depletions
L-tyrosine contributes to (+)-3,4-methylenedioxymethamphetamine-induced serotonin depletions
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DOI：
10.1523/jneurosci.3353-05.2006
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发表时间：
2006-01-04
影响因子：
5.3
通讯作者：
Yamamoto, BK
中科院分区：
文献类型：
--
作者：
Breier, JM;Bankson, MG;Yamamoto, BK
（+）-3,4-亚甲基二氧基甲基苯丙胺（MDMA）诱导的5-HT末端损伤的具体机制尚不清楚。尽管假设多巴胺（DA）和DA衍生的自由基在介导这种损伤中起作用，但MDMA在由DA神经元稀疏支配的大脑区域产生5-羟色胺长期消耗的原因仍不清楚。我们假设DA生物合成的前体酪氨酸介导mdma诱导的5-羟色胺消耗。在MDMA神经毒性剂量下，纹状体细胞外酪氨酸浓度增加了5倍，海马细胞外酪氨酸浓度增加了2.5倍。体外实验结果表明，在促氧化条件下，l -酪氨酸可以被非酶羟化成DA前体l -3,4-二羟基苯丙氨酸（DOPA）。在MDMA给药期间，l -酪氨酸局部输注到纹状体或海马，增强了MDMA后细胞外DA的急性增加和5-HT的长期消耗。芳香氨基酸脱羧酶（AADC）抑制剂间羟基苄基肼的共输注减弱了海马的这些作用，降低了纹状体的基底细胞外DA。相反，将酪氨酸羟化酶抑制剂α -甲基-对酪氨酸反透析入海马并不影响mdma诱导的细胞外DA增加或5-羟色胺的长期消耗。这些结果表明，MDMA增加了大脑中酪氨酸的浓度，通过非酶、酪氨酸羟化酶独立、酪氨酸羟化成多巴，随后通过AADC转化成DA，从而导致5-羟色胺的长期消耗。总的来说，研究结果表明MDMA通过增加酪氨酸并最终在5-HT末端转化为DA来消耗5-HT。
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.