Schwarting R K, Sedelis M, Hofele K, Auburger G W, Huston J P
Institute of Physiological Psychology I, and Center for Biological and Medical Research, Heinrich-Heine-University of Düsseldorf, Germany.
Neurotox Res. 1999 Sep;1(1):41-56. doi: 10.1007/BF03033338.
The neurotoxin MPTP can damage dopamine systems in the brains of rodents, cats, or monkeys, and is therefore widely used to model degenerative processes that underlie human Parkinson's disease. Here, we investigated the relationships between behavioral and neurochemical effects of systemic MPTP treatment in C57Bl/6 and Balb/c mice. Initially, different doses of MPTP were used to determine which of them might be useful to establish severe striatal dopamine depletions. These data showed that four injections of 20mg/kg at two hour intervals, were more efficient than 10 or 15mg/kg per injection. However, this dose was not usable due to its severe lethality in females. In contrast, 4x 15mg/kg had a low risk of lethality and led to substantial dopamine depletions, which were more severe in the neostriatum than the ventral striatum, and more severe in C57 than in Balb mice. In the first open field test, which was performed two hours after the last injection, this treatment led to severe behavioral inactivation in all parameters taken (distance and speed of locomotion, peripheral activity, frequency and duration of rearing). This effect was seen in both strains and gender. Thereafter, recovery differed between strains, since Balb mice, which had sustained the smaller lesions, had completely recovered on the subsequent day, whereas similar recovery took longer in C57 mice. On the fourth day, all groups appeared largely normal; however, the measure of rearing behavior still showed a deficit in C57 mice. This deficit on day 4 was correlated with neostriatal dopamine depletion; that is, the larger the lesion, the less the number and duration of rearings. Interestingly, these relationships were also observed with respect to ventral striatal dopamine damage, which was correlated with the rearing deficit not only on day 4, but also on day 1. These data will be discussed with respect to mechanisms of toxicity, functional recovery, and the function of striatal dopamine systems.
神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）可损害啮齿动物、猫或猴子大脑中的多巴胺系统，因此被广泛用于模拟人类帕金森病潜在的退行性过程。在此，我们研究了C57Bl/6和Balb/c小鼠全身MPTP治疗的行为和神经化学效应之间的关系。最初，使用不同剂量的MPTP来确定其中哪些剂量可能有助于造成严重的纹状体多巴胺耗竭。这些数据表明，每隔两小时注射4次20mg/kg比每次注射10或15mg/kg更有效。然而，由于该剂量对雌性具有严重致死性，因此不可用。相比之下，4×15mg/kg的致死风险较低，并导致大量多巴胺耗竭，新纹状体中的耗竭比腹侧纹状体更严重，C57小鼠比Balb小鼠更严重。在最后一次注射后两小时进行的首次旷场试验中，这种治疗导致所有测量参数（运动距离和速度、外周活动、竖毛频率和持续时间）出现严重的行为失活。这种效应在两个品系和两种性别中均可见。此后，品系之间的恢复情况有所不同，因为损伤较小的Balb小鼠在随后一天完全恢复，而C57小鼠的类似恢复则需要更长时间。在第四天，所有组看起来基本正常；然而，竖毛行为测量仍显示C57小鼠存在缺陷。第4天的这种缺陷与新纹状体多巴胺耗竭相关；也就是说，损伤越大，竖毛的次数和持续时间越少。有趣的是，关于腹侧纹状体多巴胺损伤也观察到了这些关系，其不仅与第4天的竖毛缺陷相关，而且与第1天的竖毛缺陷相关。将针对毒性机制、功能恢复以及纹状体多巴胺系统的功能来讨论这些数据。
