School of Biomedical Sciences, Institute of Neuroscience, University of Nottingham, Nottingham, UK.
J Psychopharmacol. 2010 Feb;24(2):267-74. doi: 10.1177/0269881109348163. Epub 2009 Dec 4.
The mechanism by which 3,4-methylenedioxymethamphetamine (MDMA) produces 5-hydroxytryptamine (5-HT, serotonin) neurotoxicity has been suggested to involve an acute release of tyrosine and its non-enzymatic conversion to dopamine. To determine whether brain tyrosine availability is important in MDMA-induced neurotoxicity, brain tyrosine was acutely depleted with a tyrosine-free amino acid mixture (1 g/kg intraperitoneal; twice 1 h apart) which was administered prior to an injection of MDMA (12.5 mg/kg intraperitoneal). A small increase in both the hippocampal and striatal tyrosine concentration occurred in control rats treated with MDMA. The tyrosine-free amino acid mixture significantly decreased tyrosine levels by more than 50% in both brain regions 2 h after injection of either MDMA or saline. MDMA significantly reduced brain 5-HT content 2 h later, but this was of a similar magnitude in control and tyrosine-depleted groups. The long-term neurotoxic 5-HT loss in the hippocampus induced two weeks after MDMA administration was unaltered by the tyrosine-free amino acid mixture. Striatal dopamine content was unaffected by acute MDMA in all groups, while the tyrosine-free amino acid mixture given with MDMA significantly decreased striatal dopamine content 2 weeks later. The tyrosine-free amino acid mixture given alone had no affect on rectal body temperature but attenuated the duration of MDMA-induced hyperthermia. The results confirmed the ability of systemic MDMA to acutely increase brain tyrosine content, but also indicated that a marked acute reduction of brain tyrosine does not directly affect either immediate 5-HT release (as measured by tissue depletion) or long-term hippocampal serotonergic neurotoxicity produced by MDMA.
3,4-亚甲二氧基甲基苯丙胺 (MDMA) 导致 5-羟色胺 (5-HT，血清素) 神经毒性的机制被认为涉及酪氨酸的急性释放及其非酶促转化为多巴胺。为了确定脑酪氨酸的可用性是否对 MDMA 诱导的神经毒性很重要，我们使用酪氨酸无氨基酸混合物（1 g/kg 腹腔内；2 次，间隔 1 小时）急性耗尽脑酪氨酸，然后再注射 MDMA（12.5 mg/kg 腹腔内）。在接受 MDMA 治疗的对照组大鼠中，海马和纹状体中的酪氨酸浓度均略有增加。在注射 MDMA 或生理盐水后 2 小时，酪氨酸无氨基酸混合物使两个脑区的酪氨酸水平显著降低超过 50%。2 小时后，MDMA 显著降低了脑 5-HT 含量，但在对照组和酪氨酸耗尽组中，这一效应相似。2 周后，MDMA 给药后引起的长期神经毒性 5-HT 丢失在海马体中没有变化。急性 MDMA 对所有组的纹状体多巴胺含量均无影响，而与 MDMA 一起给予的酪氨酸无氨基酸混合物在 2 周后显著降低了纹状体多巴胺含量。单独给予酪氨酸无氨基酸混合物对直肠体温没有影响，但减轻了 MDMA 引起的高热持续时间。结果证实了全身 MDMA 急性增加脑酪氨酸含量的能力，但也表明，脑酪氨酸的明显急性减少不会直接影响 MDMA 引起的即刻 5-HT 释放（如通过组织耗竭测量）或长期海马体 5-羟色胺能神经毒性。
