Kilbourn M R, Sherman P, Abbott L C
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
Synapse. 1998 Oct;30(2):205-10. doi: 10.1002/(SICI)1098-2396(199810)30:2<205::AID-SYN10>3.0.CO;2-0.
The effects of MPTP treatment (4 x 10 mg/kg, 2-h intervals) on in vivo striatal binding of (+)-alpha-[3H]dihydrotetrabenazine ((+)-[3H]DTBZ) to the vesicular monoamine transporter type 2 (VMAT2) were examined in wild type (+,+) and tottering (tg/tg) mice of the C57BL/6J strain. The tottering mutant has been previously characterized as having hyperinnervation of noradrenergic terminals in the brain, with increased concentrations of norepinephrine and increased numbers of VMAT2 binding sites. In wild-type mice, MPTP caused a significant decrease in specific striatal (+)-[3H]DTBZ binding in both males (-71%) and females (-57%), consistent with dopaminergic terminal losses. In the tottering mice, the neurotoxic effects of MPTP were diminished, with smaller losses of (+)-[3H]DTBZ binding observed both in males (-45%) and females (-26%). These results are consistent with the hypothesis that vesicular storage (as a result of hyperinnervation) offers neuroprotection toward MPTP toxicity, although the confounding effects of increases in norepinephrine concentrations or changes in calcium ion channel function (both also characteristics of the tottering mutant) cannot be ruled out. The tottering mutant does, however, offer another animal model to examine the biochemical features responsible for MPTP toxicity.
在C57BL/6J品系的野生型（+/+）和蹒跚（tg/tg）小鼠中，研究了MPTP治疗（4×10mg/kg，间隔2小时）对体内纹状体中（+）-α-[3H]二氢丁苯那嗪（（+）-[3H]DTBZ）与2型囊泡单胺转运体（VMAT2）结合的影响。先前已将蹒跚突变体表征为大脑中去甲肾上腺素能终末的神经支配过度，去甲肾上腺素浓度增加且VMAT2结合位点数量增多。在野生型小鼠中，MPTP导致雄性（-71%）和雌性（-57%）纹状体中特异性（+）-[3H]DTBZ结合显著减少，这与多巴胺能终末损失一致。在蹒跚小鼠中，MPTP的神经毒性作用减弱，在雄性（-45%）和雌性（-26%）中观察到（+）-[3H]DTBZ结合的损失较小。这些结果与以下假设一致，即囊泡储存（由于神经支配过度）对MPTP毒性具有神经保护作用，尽管不能排除去甲肾上腺素浓度增加或钙离子通道功能变化（这两者也是蹒跚突变体的特征）的混杂效应。然而，蹒跚突变体确实提供了另一种动物模型来研究导致MPTP毒性的生化特征。
