Goñi-Allo Beatriz, Puerta Elena, Mathúna Brian O, Hervias Isabel, Lasheras Berta, de la Torre Rafael, Aguirre Norberto
Department of Pharmacology, School of Medicine, University of Navarra, c/ Irunlarrea 1, 31008 Pamplona, Spain.
Neuropharmacology. 2008 Apr;54(5):885-900. doi: 10.1016/j.neuropharm.2008.01.007. Epub 2008 Feb 3.
The mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonergic (5-HT) toxicity remain unclear. It has been suggested that MDMA depletes 5-HT by increasing brain tyrosine levels, which via non-enzymatic hydroxylation leads to DA-derived free radical formation. Because this hypothesis assumes the pre-existence of hydroxyl radicals, we hypothesized that MDMA metabolism into pro-oxidant compounds is the limiting step in this process. Acute hyperthermia, plasma tyrosine levels and concentrations of MDMA and its main metabolites were higher after a toxic (15 mg/kg i.p.) vs. a non-toxic dose of MDMA (7.5mg/kg i.p.). The administration of a non-toxic dose of MDMA in combination with l-tyrosine (0.2 mmol/kg i.p.) produced a similar increase in serum tyrosine levels to those found after a toxic dose of MDMA; however, brain 5-HT content remained unchanged. The non-toxic dose of MDMA combined with a high dose of tyrosine (0.5 mmol/kg i.p.), caused long-term 5-HT depletions in rats treated at 21.5 degrees C but not in those treated at 15 degrees C, conditions known to decrease MDMA metabolism. Furthermore, striatal perfusion of MDMA (100 microM for 5h) combined with tyrosine (0.5 mmol/kg i.p.) in hyperthermic rats did not cause 5-HT depletions. By contrast, rats treated with the non-toxic dose of MDMA under heating conditions or combined with entacapone or acivicin, which interfere with MDMA metabolism or increase brain MDMA metabolite availability respectively, showed significant reductions of brain 5-HT content. Altogether, these data indicate that although tyrosine may contribute to MDMA-induced toxicity, MDMA metabolism appears to be the limiting step.
3,4-亚甲基二氧甲基苯丙胺（摇头丸）所致5-羟色胺（5-HT）毒性的潜在机制尚不清楚。有人提出，摇头丸通过增加脑内酪氨酸水平来消耗5-HT，酪氨酸经非酶促羟基化导致多巴胺衍生的自由基形成。由于该假说假定预先存在羟基自由基，我们推测摇头丸代谢为促氧化化合物是这一过程中的限速步骤。给予毒性剂量（腹腔注射15mg/kg）的摇头丸后，急性体温过高、血浆酪氨酸水平以及摇头丸及其主要代谢产物的浓度均高于非毒性剂量（腹腔注射7.5mg/kg）。给予非毒性剂量的摇头丸并联合L-酪氨酸（腹腔注射0.2mmol/kg）后，血清酪氨酸水平升高幅度与给予毒性剂量摇头丸后相似；然而，脑内5-HT含量并未改变。非毒性剂量的摇头丸联合高剂量酪氨酸（腹腔注射0.5mmol/kg），在21.5℃条件下处理的大鼠中导致长期5-HT耗竭，但在15℃条件下处理的大鼠中则未出现，已知15℃可降低摇头丸代谢。此外，在体温过高的大鼠中，纹状体灌注摇头丸（100μM，持续5小时）并联合酪氨酸（腹腔注射0.5mmol/kg）并未导致5-HT耗竭。相比之下，在加热条件下给予非毒性剂量摇头丸或联合恩他卡朋或阿西维辛（分别干扰摇头丸代谢或增加脑内摇头丸代谢产物可用性）处理的大鼠，脑内5-HT含量显著降低。总之，这些数据表明，尽管酪氨酸可能参与摇头丸所致毒性，但摇头丸代谢似乎是限速步骤。
