Bowyer J F, Davies D L, Schmued L, Broening H W, Newport G D, Slikker W, Holson R R
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas.
J Pharmacol Exp Ther. 1994 Mar;268(3):1571-80.
The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subsequently, rats saved by hypothermic intervention have greater depletion of striatal DA at an earlier time of onset (18 hr or less post-METH) than do METH-exposed rats that do not attain such high temperatures. Striatal damage was present 3 days post-METH in these hyperthermic rats, as assessed by silver degeneration of terminals and increases in the astrocytes that express glial fibrillary acidic protein immunoreactivity. By contrast, alterations in the number of [3H]dizoclipine (MK-801) binding sites in cortical or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and maximal body temperature correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 58), which suggests a role for hyperthermia in METH neurotoxicity. However, hyperthermia (alone or with haloperidol present) induced by high ambient temperatures did not deplete striatal DA in the absence of METH. Haloperidol, diazepam and MK-801 all reduced METH-induced striatal DA depletion to a degree predicted by their inhibition of hyperthermia and increased ambient temperature abolished their neuroprotection. Although an interleukin-1 receptor antagonist reduced maximal body temperature enough to lower the lethality rate, it did not reduce the temperature sufficiently to block METH neurotoxicity. It was concluded that short- and long-term decreases in striatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia alone. In addition, several agents that block DA depletions do so by inhibiting METH-induced hyperthermia. Finally, the results suggested a role for interleukin-1 in the extreme hyperthermia and lethality produced by METH.
甲基苯丙胺（METH）给药后纹状体多巴胺（DA）的耗竭与METH诱导的体温过高有关。本研究进一步探讨了METH诱导的体温过高、神经毒性（纹状体DA耗竭）与预防METH神经毒性的化合物之间的关系。通常情况下，暴露于METH的大鼠体温超过41.3摄氏度时会死亡，但这种体温过高的大鼠可通过低温干预挽救。随后，通过低温干预挽救的大鼠在发病早期（METH给药后18小时或更短时间）纹状体DA的耗竭程度比未达到如此高温的METH暴露大鼠更大。通过终末银染色变性以及表达胶质纤维酸性蛋白免疫反应性的星形胶质细胞增加来评估，这些体温过高的大鼠在METH给药后3天出现纹状体损伤。相比之下，在METH给药后1、3或14天，未检测到皮质或纹状体膜中[3H]地佐环平（MK-801）结合位点数量的改变。实验表明，METH给药后3天的平均体温和最高体温与纹状体DA浓度密切相关（r = -0.77，n = 58），这表明体温过高在METH神经毒性中起作用。然而，在没有METH的情况下，高环境温度诱导的体温过高（单独或伴有氟哌啶醇）并未使纹状体DA耗竭。氟哌啶醇、地西泮和MK-801均将METH诱导的纹状体DA耗竭降低到其抑制体温过高所预测的程度，而环境温度升高消除了它们的神经保护作用。尽管白细胞介素-1受体拮抗剂将最高体温降低到足以降低致死率的程度，但它并未将体温降低到足以阻断METH神经毒性的程度。得出的结论是，纹状体DA水平的短期和长期降低取决于METH暴露期间产生的体温过高程度，但不能仅由体温过高产生。此外，几种阻断DA耗竭的药物是通过抑制METH诱导的体温过高来实现这一点的。最后，结果表明白细胞介素-1在METH产生的极度体温过高和致死率中起作用。
