Endocrine and Neurochemical Effects of 3,4-Methylenedioxymethamphetamine and Its Stereoisomers in Rhesus Monkeys
Endocrine and Neurochemical Effects of 3,4-Methylenedioxymethamphetamine and Its Stereoisomers in Rhesus Monkeys
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DOI：
10.1124/jpet.110.166595
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发表时间：
2010-08-10
影响因子：
3.5
通讯作者：
Howell, L. L.
中科院分区：
文献类型：
--
作者：
Murnane, K. S.;Fantegrossi, W. E.;Howell, L. L.
3,4-亚甲基二氧甲基苯丙胺（MDMA）是一种苯丙胺衍生物，在人体中引起复杂的生物效应。这种现象的一个可能的机制是外消旋MDMA由两种具有不同药理作用的立体异构体组成。为了支持这一观点，研究表明，R(-)- mdma倾向于具有类似致幻剂的作用，而S(+)- mdma倾向于具有类似精神运动兴奋剂的作用。然而，对于这些立体异构体是否会产生不同的内分泌和神经化学作用，人们知之甚少。在本研究中，研究人员在4只恒河猴体内以1-3 mg/kg的剂量静脉给药，评估了每种立体异构体和外消旋体的内分泌和神经化学效应。具体来说，采用荧光酶联免疫吸附法评估血浆催乳素浓度，采用体内微透析评估背纹状体细胞外多巴胺和血清素浓度。R(-)- mdma显著提高血浆催乳素水平，而S(+)- mdma不显著提高血浆催乳素水平，S、R(+/-)- mdma对其各组分立体异构体的影响介于中间。虽然S(+)-MDMA不改变催乳素水平，但它确实显著增加细胞外血清素浓度。此外，S(+)- mdma显著增加多巴胺浓度，而R(-)- mdma不显著增加。此外，在催乳素实验中，外消旋体的作用是中间的每一个立体异构体。这些研究表明，MDMA的立体异构体会产生质的不同的内分泌和神经化学效应，加强了这些立体异构体的差异可能是MDMA外消旋混合物在人体中产生复杂生物效应的机制的推断。
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that elicits complex biological effects in humans. One plausible mechanism for this phenomenon is that racemic MDMA is composed of two stereoisomers that exhibit qualitatively different pharmacological effects. In support of this, studies have shown that R(-)-MDMA tends to have hallucinogen- like effects, whereas S(+)-MDMA tends to have psychomotor stimulant-like effects. However, relatively little is known about whether these stereoisomers engender different endocrine and neurochemical effects. In the present study, the endocrine and neurochemical effects of each stereoisomer and the racemate were assessed in four rhesus monkeys after intravenous delivery at doses (1-3 mg/kg) that approximated voluntary self-administration by rhesus monkeys and human recreational users. Specifically, fluorescence-based enzyme-linked immunosorbent assay was used to assess plasma prolactin concentrations, and in vivo microdialysis was used to assess extracellular dopamine and serotonin concentrations in the dorsal striatum. R(-)-MDMA, but not S(+)-MDMA, significantly increased plasma prolactin levels and the effects of S, R(+/-)-MDMA were intermediate to each of its component stereoisomers. Although S(+)-MDMA did not alter prolactin levels, it did significantly increase extracellular serotonin concentrations. In addition, S(+)-MDMA, but not R(-)-MDMA, significantly increased dopamine concentrations. Furthermore, as in the prolactin experiment, the effects of the racemate were intermediate to each of the stereoisomers. These studies demonstrate the stereoisomers of MDMA engender qualitatively different endocrine and neurochemical effects, strengthening the inference that differences in these stereoisomers might be the mechanism producing the complex biological effects of the racemic mixture of MDMA in humans.