Johnson M P, Conarty P F, Nichols D E
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
Eur J Pharmacol. 1991 Jul 23;200(1):9-16. doi: 10.1016/0014-2999(91)90659-e.
The ability of several 3,4-methylenedioxymethamphetamine (MDMA) analogues to inhibit the uptake of [3H]serotonin (5-HT), dopamine (DA) and norepinephrine (NE) into synaptosomes was examined. In addition, the ability of the compounds to inhibit the uptake of [3H]5-HT and DA into synaptosomes from rats pretreated with reserpine (5 mg/kg i.p., 16 h pretreatment) was compared to control experiments. All of the test compounds were found to be potent releasers of non-vesicular 5-HT (the reserpine IC50 was significantly smaller than the control IC50). The range of 5-HT inhibitory activity corresponds well to the small range of ED50 values of the test compounds to substitute in drug discrimination experiments with animals trained to discriminate MDMA or S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane (S-MBDB) from saline. In contrast, there was a wide range of potency for the inhibition of NE and DA uptake. In addition, several of the analogues appeared to be pure uptake inhibitors of DA while others were found to be releasers of non-vesicular DA. Several of the compounds were very selective for 5-HT over DA or NE uptake inhibition, including 3-methoxy-4-methylamphetamine (MMA) and 5-methoxy-6-methyl-2-aminoindan (MMAI). A correlation was noted between the 5-HT neurotoxic potential of some of the test compounds and their relative ability to induce a release of non-vesicular DA. The potential catechol metabolites of the methylenedioxy-substituted compounds also showed potent monoamine releasing properties, suggesting that metabolism may play a role in the neurotoxic actions of some of these drugs. The present data support the hypothesis that drug-stimulated non-vesicular 5-HT release is primarily responsible for the discriminative cue of MDMA.
研究了几种3,4-亚甲基二氧甲基苯丙胺（摇头丸）类似物抑制[3H]5-羟色胺（5-HT）、多巴胺（DA）和去甲肾上腺素（NE）摄入突触体的能力。此外，将这些化合物抑制利血平（腹腔注射5mg/kg，预处理16小时）预处理大鼠突触体中[3H]5-HT和DA摄入的能力与对照实验进行了比较。所有测试化合物均被发现是有效的非囊泡性5-HT释放剂（利血平IC50显著小于对照IC50）。5-HT抑制活性范围与测试化合物在动物辨别实验中替代摇头丸或S-(+)-N-甲基-1-(1,3-苯并二氧杂环戊烯-5-基)-2-氨基丁烷（S-MBDB）与生理盐水的ED50值的小范围很好地对应。相比之下，NE和DA摄入抑制的效力范围很广。此外，一些类似物似乎是DA的纯摄入抑制剂，而其他一些则被发现是非囊泡性DA的释放剂。几种化合物对5-HT的选择性高于DA或NE摄入抑制，包括3-甲氧基-4-甲基苯丙胺（MMA）和5-甲氧基-6-甲基-2-氨基茚满（MMAI）。注意到一些测试化合物的5-HT神经毒性潜力与其诱导非囊泡性DA释放的相对能力之间存在相关性。亚甲二氧基取代化合物的潜在儿茶酚代谢物也表现出强大的单胺释放特性，表明代谢可能在其中一些药物的神经毒性作用中起作用。目前的数据支持这样的假设，即药物刺激的非囊泡性5-HT释放主要负责摇头丸的辨别线索。
