Kirik D, Rosenblad C, Björklund A
Department of Physiology and Neuroscience, Lund University, Sölvegatan 17, Lund, 223 62, Sweden.
Exp Neurol. 1998 Aug;152(2):259-77. doi: 10.1006/exnr.1998.6848.
Partial lesions of the nigrostriatal dopamine system have been investigated with respect to their ability to induce consistent long-lasting deficits in movement initiation and skilled forelimb use. In eight different lesion groups 6-hydroxydopamine (6-OHDA) was injected at one, two, three, or four sites into the lateral sector of the right striatum, in a total dose of 20-30 microgram. Impairments in movement initiation in a forelimb stepping test, and in skilled paw use in a paw-reaching test, was seen only in animals where the severity of the lesion exceeded a critical threshold, which was different for the different tests used: single (1 x 20 microgram) or two-site (2 x 10 microgram) injections into the striatum had only small affects on forelimb stepping, no effect on skilled paw use. More pronounced deficits were obtained in animals where the same total dose of 6-OHDA was distributed over three or four sites along the rostro-caudal extent of the lateral striatum or where the injections were made close to the junction of the globus pallidus. The results show that a 60-70% reduction in tyrosine hydroxylase (TH)-positive fiber density in the lateral striatum, accompanied by a 50-60% reduction in TH-positive cells in substantia nigra (SN), is sufficient for the induction of significant impairment in initiation of stepping. Impaired skilled paw-use, on the other hand, was obtained only with a four-site (4 x 7 microgram) lesion, which induced 80-95% reduction in TH fiber density throughout the rostrocaudal extent of the lateral striatum and a 75% loss of TH-positive neurons in SN. Drug-induced rotation, by contrast, was observed also in animals with more restricted presymptomatic lesions. The results indicate that the four-site intrastriatal 6-OHDA lesion may be a relevant model of the neuropathology seen in parkinsonian patients in a manifest symptomatic stage of the disease and may be particularly useful experimentally since it leaves a significant portion of the nigrostriatal projection intact which can serve as a substrate for regeneration and functional recovery in response to growth promoting and neuroprotective agents.
黑质纹状体多巴胺系统的部分损伤已就其诱导运动起始和熟练前肢使用持续长期缺陷的能力进行了研究。在八个不同的损伤组中，将6-羟基多巴胺（6-OHDA）以20-30微克的总剂量注射到右侧纹状体外侧区的一个、两个、三个或四个部位。仅在损伤严重程度超过临界阈值的动物中观察到前肢踏步试验中运动起始的损害以及抓物试验中熟练爪子使用的损害，不同试验的临界阈值不同：单次（1×20微克）或两点（2×10微克）注射到纹状体对前肢踏步只有微小影响，对熟练爪子使用无影响。在将相同总剂量的6-OHDA沿外侧纹状体的前后范围分布在三个或四个部位或注射靠近苍白球交界处的动物中获得了更明显的缺陷。结果表明，外侧纹状体中酪氨酸羟化酶（TH）阳性纤维密度降低60-70%，同时黑质（SN）中TH阳性细胞减少50-60%，足以诱导踏步起始的显著损害。另一方面，只有四点（4×7微克）损伤导致熟练爪子使用受损，该损伤在外侧纹状体的整个前后范围内诱导TH纤维密度降低80-95%，SN中TH阳性神经元损失75%。相比之下，在有更局限的症状前损伤的动物中也观察到药物诱导的旋转。结果表明，四点纹状体内6-OHDA损伤可能是帕金森病患者疾病明显症状阶段所见神经病理学的相关模型，并且在实验上可能特别有用，因为它使黑质纹状体投射的很大一部分保持完整，这可以作为对生长促进剂和神经保护剂作出反应的再生和功能恢复的底物。
