Aguirre N, Barrionuevo M, Lasheras B, Del Río J
Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain.
J Pharmacol Exp Ther. 1998 Sep;286(3):1159-65.
Our study was aimed at analyzing the basis for the apparent lack of perinatal sensitivity to the serotonergic neurotoxin 3, 4-methylenedioxymethamphetamine (MDMA, "ecstasy"). MDMA (20 mg/kg s. c.) repeatedly administered to rat dams during gestation, did not affect [3H]paroxetine-labeled serotonin (5-HT) transporter density and 5-HT content in the offspring. A single dose of MDMA was then given to pups, not exposed prenatally to MDMA, at different postnatal ages (PND14, 21, 28 and 35). Long-term significant reductions in 5-HT levels in all the brain regions examined were only found at PND35. In a different set of experiments, MDMA administered at PND21 alone or in combination with (R)-1-(2, 5-dimethoxy-4-iodophenyl)2-aminopropane (R-DOI, 0.5 mg/kg s.c.), or L-3,4-dihydroxyphenylalanine (L-DOPA, 80 mg/kg s.c.), caused a significant hyperthermia in the pups. However, only L-DOPA followed by MDMA caused a lasting reduction of 5-HT levels and 5-HT transporter density in the hippocampus and in the frontal cortex. In adult animals, no change in 5-HT levels and 5-HT transporter density in different brain regions was either found when MDMA was given to rats previously lesioned with 6-hydroxydopamine, but a significant reduction was again found in the lesioned animals receiving MDMA in combination with L-DOPA. These results appear to indicate that the hyperthermia induced by MDMA is not sufficient to produce lasting neurotoxic effects on the serotonergic system, at least at PND21, and support an important role for dopamine in the mechanism of neurotoxicity of MDMA, suggesting that an already developed dopaminergic system is necessary for the expression of the serotonergic deficits.
我们的研究旨在分析围产期对血清素能神经毒素3,4-亚甲基二氧甲基苯丙胺（摇头丸，MDMA）明显缺乏敏感性的原因。在妊娠期间对大鼠母体反复皮下注射MDMA（20mg/kg），并未影响子代中[3H]帕罗西汀标记的血清素（5-HT）转运体密度和5-HT含量。然后，在不同的出生后年龄（出生后第14、21、28和35天）给未在产前接触过MDMA的幼崽单次注射MDMA。仅在出生后第35天，在所检查的所有脑区中发现5-HT水平长期显著降低。在另一组实验中，在出生后第21天单独给予MDMA或与（R）-1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷（R-DOI，0.5mg/kg皮下注射）或L-3,4-二羟基苯丙氨酸（L-DOPA，80mg/kg皮下注射）联合给予MDMA，会导致幼崽明显体温过高。然而，只有先给予L-DOPA再给予MDMA会导致海马体和额叶皮质中5-HT水平和5-HT转运体密度持续降低。在成年动物中，当给先前用6-羟基多巴胺损伤的大鼠注射MDMA时，不同脑区的5-HT水平和5-HT转运体密度没有变化，但在接受MDMA与L-DOPA联合治疗的损伤动物中再次发现显著降低。这些结果似乎表明，至少在出生后第21天，MDMA诱导的体温过高不足以对血清素能系统产生持久的神经毒性作用，并支持多巴胺在MDMA神经毒性机制中的重要作用，表明已发育的多巴胺能系统对于血清素能缺陷的表达是必要的。
