Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine.
Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine.
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DOI：
10.1016/j.neuropharm.2017.08.033
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发表时间：
2018-05-15
影响因子：
4.7
通讯作者：
Kuhn DM
中科院分区：
文献类型：
--
作者：
Anneken JH;Angoa-Perez M;Sati GC;Crich D;Kuhn DM
甲基苯丙胺和甲氧麻黄酮是易滥用的特制药物，它们在化学结构和神经药理作用上有广泛的相似之处。然而，这些药物在一个显著的方面有所不同：甲基苯丙胺会引起多巴胺神经毒性，而甲氧麻黄酮不会。从结构上看，甲氧麻黄酮有一个β-酮基和一个4-甲基环加成，这两种物质都不含甲基苯丙胺。我们以前的研究发现，只含有β-酮取代基的美卡西酮具有神经毒性，而只含有4-甲基环取代基的4-甲基苯丙胺对神经毒性最小。在目前的研究中，假设与这些化合物相关的不同的神经毒性潜力是由药物释放的多巴胺池介导的，甲基苯丙胺可能比甲苯丙酮、美卡西酮和4-甲基苯丙胺更容易进入多巴胺池。为了验证这一假设，已知会增加多巴胺和甲基苯丙胺神经毒性可释放池的化合物L-多巴和帕吉林与甲氧麻黄酮、4-甲基苯丙胺和甲卡西酮联合使用。甲基苯丙胺也进行了测试，因为它有能力增加可释放的多巴胺。这三种方案都显著增强了纹状体对4-甲基苯丙胺的神经毒性和神经胶质细胞的反应性。仅L多巴可增强美卡西酮的神经毒性和神经胶质细胞的反应性。当与L多巴或帕吉林联合使用时，甲麻酮仍无神经毒性。每种设计药物的体温效应不会因联合治疗而改变。这些结果支持这样的结论，即4-甲基甲基苯丙胺、美卡西酮和甲基苯丙胺的神经毒性可能受到β-酮和4-甲基取代基所致的药物释放的多巴胺池的不同调节，但尽管该库中的多巴胺池大幅增加，甲氧麻黄酮仍然没有神经毒性。
Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a β-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the β-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4-methylmethamphetamine. To test this hypothesis, L-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by L-DOPA. Mephedrone remained non-neurotoxic when combined with either L-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4-methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to β-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine.
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影响因子：
4.7
作者：
Anneken JH;Angoa-Pérez M;Kuhn DM
通讯作者：
Kuhn DM
影响因子：
6.1
作者：
Halpin, Laura E.;Collins, Stuart A.;Yamamoto, Bryan K.
通讯作者：
Yamamoto, Bryan K.
影响因子：
3.7
作者：
Gołembiowska K;Jurczak A;Kamińska K;Noworyta-Sokołowska K;Górska A
通讯作者：
Górska A
影响因子：
3.8
作者：
den Hollander, Bjornar;Sundstrom, Mira;Kankuri, Esko
通讯作者：
Kankuri, Esko
影响因子：
4.7
作者：
Harun, Rashed;Hare, Kristin M.;Wagner, Amy K.
通讯作者：
Wagner, Amy K.