Persistence of tolerance to methamphetamine-induced monoamine deficits
Persistence of tolerance to methamphetamine-induced monoamine deficits
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DOI：
10.1016/j.ejphar.2006.11.045
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发表时间：
2007-03-15
影响因子：
5
通讯作者：
Wilkins, Diana G.
中科院分区：
文献类型：
--
作者：
Danaceau, Jonathan P.;Deering, Cassandra E.;Wilkins, Diana G.
甲基苯丙胺是一种高度成瘾性和强效兴奋剂，近年来其使用量显着增加。除了与甲基苯丙胺滥用相关的严重行为和社会后果外，甲基苯丙胺还可对大鼠的单胺能神经末梢造成持续性损害，这可以通过单胺浓度或限速合成酶、酪氨酸羟化酶和色氨酸羟化酶的活性来测量。然而，重复、亚神经毒性剂量的甲基苯丙胺可能会导致大鼠对多次高剂量甲基苯丙胺给药的神经毒性作用产生抵抗力；这种现象被称为宽容。本研究调查了使用逐渐增加剂量的甲基苯丙胺进行预处理所引起的耐受性的持续性。大鼠接受低剂量、逐步递增的甲基苯丙胺预处理数天，然后在不同的恢复期后接受高剂量甲基苯丙胺攻击。结果显示，对单胺能缺乏的耐受性至少持续一周，但在 31 天后完全消除。在最后一次甲基苯丙胺攻击注射后2小时，甲基苯丙胺或其主要代谢物苯丙胺的分布在甲基苯丙胺预处理的动物和盐水预处理的动物之间没有差异，并且额叶皮层、海马或纹状体之间的甲基苯丙胺浓度没有区域差异。我们还观察到，虽然甲基苯丙胺预处理减轻了高剂量甲基苯丙胺激发引起的高热，但对该方案的耐受性的发展并不需要显着减少甲基苯丙胺引起的高热。 (c) 2007 年 Elsevier B.V. 出版
Methamphetamine is a highly addictive and potent stimulant, the use of which has increased significantly in recent years. In addition to the severe behavioral and societal consequences associated with methamphetamine abuse, methamphetamine can cause persistent damage to monoaminergic nerve terminals in rats, as measured by either monoamine concentrations or activity of the rate limiting synthetic enzymes, tyrosine hydroxylase and tryptophan hydroxylase. Repeated, sub-neurotoxic doses of methamphetamine, however, can cause rats to become resistant to the neurotoxic effects of multiple high-dose administrations of methamphetamine; a phenomenon known as tolerance. This study investigates the persistence of tolerance evoked by pretreatment with escalating-dose administrations of metbamphetamine. Rats were pretreated over several days with low, escalating doses of methamphetamine, followed by high-dose methamphetamine challenge after variable recovery periods. Results revealed that tolerance to monoaminergic deficits persisted for at least one week, but was completely eliminated by 31 days. There were no differences in the distribution of methamphetamine or its major metabolite, amphetamine, between methamphetamine-pretreated animals and saline-pretreated animals 2 h after the final methamphetamine challenge injection, and there were no regional differences in methamphetamine concentrations between the frontal cortex, hippocampus or striatum. We also observed that while methamphetamine pretreatment attenuated the hyperthermia caused by the high-dose methamphetamine challenge, significant reductions in methamphetamine-induced hyperthermia were not required for the development of tolerance with this regimen. (c) 2007 Published by Elsevier B.V.