Albers D S, Sonsalla P K
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, USA.
J Pharmacol Exp Ther. 1995 Dec;275(3):1104-14.
Neurotoxic doses of methamphetamine (METH) can cause hyperthermia in experimental animals. Damage sustained to dopaminergic nerve terminals by this stimulant can be reduced by environmental cooling or by pharmacological manipulation which attenuates the hyperthermia. Many pharmacological agents with very diverse actions protect against METH-induced neuropathology. Several of these compounds, as well as drugs which do not protect, were investigated to determine if there was a relationship between protection and METH-induced hyperthermia. Mice received METH with or without concurrent administration of other drugs and core (i.e., colonic) temperature was monitored during treatment. The animals were sacrificed > or = 5 days later and neostriatal tyrosine hydroxylase activity and dopamine were measured. Core temperature was significantly elevated (> or = 2 degrees C) in mice treated with doses of METH which produced > or = 90% losses in striatal dopamine but not in mice less severally affected (only 50% loss of dopamine). Concurrent treatment of mice with METH and pharmacological agents which protected partially or completely from METH-induced toxicity also prevented the hyperthermic response (i.e., dopamine receptor antagonists, fenfluramine, dizocilpine, alpha-methyl-p-tyrosine, phenytoin, aminooxyacetic acid and propranol). These findings are consistent with the hypothesis that the hyperthermia produced by METH contributes to its neuropathology. However, studies with reserpine, a compound which dramatically lowers core temperature, demonstrated that hyperthermia per se is not a requirement for METH-induced neurotoxicity. Although core temperature was elevated in reserpinized mice treated with METH as compared with reserpinized control mice, their temperatures remained significantly lower than in nonreserpinized control mice. However, the hypothermic state produced in the reserpinized mice did not provide protection from METH-induced toxicity. These data demonstrate that hyperthermia per se contributes to but is not solely responsible for the METH-induced neuropathology.
神经毒性剂量的甲基苯丙胺（METH）可在实验动物中引起体温过高。这种兴奋剂对多巴胺能神经末梢造成的损伤可通过环境降温或通过减弱体温过高的药理学操作来减轻。许多具有非常不同作用的药理学药物可预防METH诱导的神经病理学。研究了其中几种化合物以及无保护作用的药物，以确定保护作用与METH诱导的体温过高之间是否存在关联。小鼠接受METH，同时或不同时给予其他药物，并在治疗期间监测核心（即结肠）温度。5天或5天以上后处死动物，测量新纹状体酪氨酸羟化酶活性和多巴胺。用产生纹状体多巴胺损失≥90%的METH剂量处理的小鼠，其核心温度显著升高（≥2℃），但多巴胺损失较轻（仅50%）的小鼠则不然。用可部分或完全预防METH诱导毒性的药理学药物同时处理小鼠，也可预防体温过高反应（即多巴胺受体拮抗剂、芬氟拉明、地佐环平、α-甲基-对-酪氨酸、苯妥英、氨氧乙酸和普萘洛尔）。这些发现与以下假设一致，即METH产生的体温过高导致其神经病理学。然而，对利血平（一种可显著降低核心温度的化合物）的研究表明，体温过高本身并非METH诱导神经毒性的必要条件。尽管与利血平化对照小鼠相比，用METH处理的利血平化小鼠的核心温度升高，但其温度仍显著低于未用利血平处理的对照小鼠。然而，利血平化小鼠产生的低温状态并不能预防METH诱导的毒性。这些数据表明，体温过高本身促成但并非METH诱导神经病理学唯一的原因。
