Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment
Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment
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DOI：
10.1016/j.ejphar.2009.01.037
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发表时间：
2009-04-01
影响因子：
5
通讯作者：
Fleckenstein, Annette E.
中科院分区：
文献类型：
--
作者：
Hanson, Jarom E.;Birdsall, Elisabeth;Fleckenstein, Annette E.
反复服用大剂量甲基苯丙胺会导致持续性的多巴胺能缺陷。由于滥用甲基苯丙胺的人经常暴露于反复的大剂量给药，其反复暴露的影响值得调查。相应地，大鼠接受重复高剂量注射甲基苯丙胺的预治疗，随后在7天或30天后用同样的神经毒性方案进行“挑战”。结果显示，最初的甲基苯丙胺治疗导致纹状体多巴胺水平、多巴胺转运体功能和囊泡单胺转运体-2功能的持续缺陷。随后的甲基苯丙胺激发治疗对这些参数没有进一步的持续性影响，如在挑战后7天评估的那样，无论最初和挑战药物暴露之间的间隔(7天或30天)。同样，在最初的药物治疗后7天给予甲基苯丙胺激发治疗，在1小时后评估，对多巴胺转运体或VMAT-2功能没有进一步的急性影响。因此，本研究描述了一种抵抗模型，可能解释为：1)存在先天不能抵抗甲基苯丙胺引起的缺陷的多巴胺能神经元；2)由于暴露于神经毒性的甲基苯丙胺而导致持续抵抗的多巴胺能神经元的存在；和/或3)突触后基底节系统的激活改变，这是阐述甲基苯丙胺诱导的多巴胺神经毒性所必需的。(C)2009爱思唯尔B.V.保留所有权利。
Repeated high-dose methamphetamine administrations can cause persistent dopaminergic deficits. As individuals abusing methamphetamine are often exposed to recurrent high-dose administration, the impact of its repeated exposure merits investigation. Accordingly, rats were pretreated with repeated high-dose injections of methamphetamine, and subsequently "challenged" with the same neurotoxic regimen 7 or 30 days later. Results revealed that the initial methamphetamine treatment caused persistent deficits in striatal dopamine levels, dopamine transporter function, and vesicular monoamine transporter-2 function. The subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, as assessed 7 days after the challenge, regardless of the interval (7 or 30 days) between the initial and challenge drug exposures. Similarly, a methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effect on dopamine transporter or VMAT-2 function, as assessed 1 h later. Thus, this study describes a model of resistance, possibly explained by: 1) the existence of dopaminergic neurons that are a priori refractory to deficits caused by methamphetamine; 2) the existence of dopaminergic neurons made persistently resistant consequent to a neurotoxic methamphetamine exposure; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced dopamine neurotoxicity. (C) 2009 Elsevier B.V. All rights reserved.