Department of Medical Toxicology, Kawasaki Medical School, Matsushima 577, Kurashiki 701-0192, Japan.
Chem Biol Interact. 2011 Mar 15;190(1):54-61. doi: 10.1016/j.cbi.2011.01.025. Epub 2011 Jan 27.
Methamphetamine (MAP) and stress both cause a variety of cardiovascular problems. Stress also increases stimulant drug-seeking or drug-taking behavior by both humans and animals. In addition to the physiological effects on circulation, metabolism, and excretion, stress affects subject's responses to stimulant drugs such as MAP. However, the mechanisms underlying the drug-stress interactions remain unknown. In the present study, we assessed the effects of stress on myocardial responses to MAP in mice. Mice were injected with MAP (30mg/kg) immediately before exposure to water-restraint stress (WRS), which has often been used as a stressor in animal experiments. The combination of MAP with WRS produced a significant increase (p<0.01) in the leakage of proteins specific to myocardial damage and the levels of cytokines IL-6, TNF-α, and IL-10. The histological findings indicated the possibility that a combination of MAP with WRS induced cardiac myocytolysis. We also examined the expression of heat shock proteins (Hsps), which have cardioprotective effects. Administration of MAP alone significantly stimulated the RNA expressions of Hsp32, 60, 70, and 90 and the protein Hsp70 in cardiac muscles, whereas the expressions due to WRS or MAP plus WRS were not increased. These results reveal the fact that exposure to WRS depresses the induction of Hsps, in particular Hsp70, due to MAP injection, following to enhance MAP-induced myocardial damage. We believe that interactions between MAP and severe stress, including environmental temperature, affect the induction of Hsps, following to susceptibility of hosts to cardiotoxicity due to the stimulant drug.
甲基苯丙胺（MAP）和压力都会导致各种心血管问题。压力也会增加人类和动物对兴奋剂药物的寻求或药物使用行为。除了对循环、代谢和排泄的生理影响外，压力还会影响主体对兴奋剂药物（如 MAP）的反应。然而，药物与压力相互作用的机制仍不清楚。在本研究中，我们评估了压力对小鼠心肌对 MAP 反应的影响。小鼠在暴露于水限制应激（WRS）之前立即注射 MAP（30mg/kg），WRS 经常被用作动物实验中的应激源。MAP 与 WRS 的组合产生了蛋白质泄漏的显著增加（p<0.01），这些蛋白质是心肌损伤的特异性蛋白，以及细胞因子 IL-6、TNF-α 和 IL-10 的水平。组织学发现表明，MAP 与 WRS 的组合可能诱导心肌细胞溶解。我们还检查了具有心脏保护作用的热休克蛋白（Hsps）的表达。单独给予 MAP 显著刺激了心脏肌肉中 Hsp32、60、70 和 90 的 RNA 表达以及 Hsp70 蛋白的表达，而 WRS 或 MAP 加 WRS 引起的表达并未增加。这些结果揭示了这样一个事实，即暴露于 WRS 会抑制由于 MAP 注射而引起的 Hsps 的诱导，特别是 Hsp70 的诱导，从而增强 MAP 诱导的心肌损伤。我们认为，MAP 与包括环境温度在内的严重压力之间的相互作用会影响 Hsps 的诱导，从而影响宿主对兴奋剂药物引起的心脏毒性的易感性。
