Rugg E L, Dunbar J S, Latimer M, Winn P
Department of Psychology, University of St Andrews, Fife, UK.
Brain Res. 1992 Sep 4;589(2):181-93. doi: 10.1016/0006-8993(92)91277-l.
The pedunculopontine tegmental nucleus (PPTg) has been shown to have cholinergic connections with the thalamus and basal ganglia. The ability of various doses of the excitotoxins (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (AMPA), folate, ibotenate, kainate, N-methyl-D-aspartate (NMDA), quinolinate and quisqualate to make lesions in the PPTg was examined, with particular reference to their ability to destroy cholinergic neurons identified using choline acetyltransferase (ChAT) immunohistochemistry. All of the toxins induced convulsive activity on recovery from surgical anesthesia and all except folate made lesions in the PPTg and surrounding structures. The size of the lesions was computed following examination of Cresyl violet stained sections. The largest lesions were made by kainate = AMPA greater than NMDA = ibotenate greater than quisqualate = quinolinate. All of the toxins destroyed cholinergic neurons, higher doses producing greater loss than lower. The ratio of cholinergic cell loss to general neuronal loss (assessed by Cresyl violet staining) was also computed, revealing marked differences between the toxins. Statistical analysis showed that there were significant differences between excitotoxins in terms of this ratio, but these were accounted for by the low dose of quinolinate (24 nmol) producing a significantly greater ratio of damage (12.18:1) than every other toxin. (Next highest ratio: quisqualate 60 nmol, 6.22:1.) Between the other toxins (kainate, AMPA, ibotenate, quisqualate, NMDA and the high dose of quinolinate) there were no statistically significant differences. Intense calcium deposits (stained by Alizarin red) were found frequently and often defined the borders of the lesion. Tyrosine hydroxylase immunohistochemistry revealed axons running below and into the area of lesioned tissue suggesting strongly that fibers were undamaged by the lesions. We conclude that in the PPTg, different excitotoxins make discriminably different lesions, both quantitatively and qualitatively. Unlike excitotoxic lesions in the basal forebrain quinolinate, not quisqualate, made the most selective lesions of cholinergic neurons and, unlike excitotoxic lesions in the septal nuclei, non-myelinated fibers were spared by ibotenate. The implications of these data for research into brainstem mechanisms of Parkinson's disease are discussed.
脑桥脚被盖核（PPTg）已被证明与丘脑和基底神经节存在胆碱能联系。研究了不同剂量的兴奋性毒素（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）（AMPA）、叶酸、鹅膏蕈氨酸、 kain 酸、N-甲基-D-天冬氨酸（NMDA）、喹啉酸和quisqualate对PPTg造成损伤的能力，特别关注它们破坏使用胆碱乙酰转移酶（ChAT）免疫组织化学鉴定的胆碱能神经元的能力。所有毒素在手术麻醉恢复后均诱发惊厥活动，除叶酸外，所有毒素均对PPTg及其周围结构造成损伤。在检查甲酚紫染色切片后计算损伤大小。最大的损伤由 kain 酸=AMPA大于NMDA=鹅膏蕈氨酸大于 quisqualate=喹啉酸造成。所有毒素均破坏胆碱能神经元，剂量越高，损失越大。还计算了胆碱能细胞损失与一般神经元损失的比率（通过甲酚紫染色评估），揭示了毒素之间的显著差异。统计分析表明，就该比率而言，兴奋性毒素之间存在显著差异，但这是由于低剂量的喹啉酸（24 nmol）产生的损伤比率（12.18:1）明显高于其他毒素所致。（次高比率：quisqualate 60 nmol，6.22:1。）在其他毒素（kain 酸、AMPA、鹅膏蕈氨酸、quisqualate、NMDA和高剂量的喹啉酸）之间没有统计学上的显著差异。经常发现强烈的钙沉积（用茜素红染色），并且常常界定损伤的边界。酪氨酸羟化酶免疫组织化学显示轴突在损伤组织区域下方并进入该区域，强烈表明纤维未被损伤破坏。我们得出结论，在PPTg中，不同的兴奋性毒素在数量和质量上造成明显不同的损伤。与基底前脑的兴奋性毒性损伤不同，喹啉酸而非 quisqualate对胆碱能神经元造成最具选择性的损伤，并且与隔核中的兴奋性毒性损伤不同，鹅膏蕈氨酸未损伤无髓纤维。讨论了这些数据对帕金森病脑干机制研究的意义。
