Da Cunha Claudio, Wietzikoski Evellyn Claudia, Ferro Marcelo Machado, Martinez Glaucia Regina, Vital Maria Aparecida Barbato Frazão, Hipólide Débora, Tufik Sergio, Canteras Newton Sabino
Laboratório de Fisiologia e Farmacologia do Sistema Nervoso Central, Departamento de Farmacologia, UFPR, Curitiba, PR, Brazil.
Behav Brain Res. 2008 Jun 3;189(2):364-72. doi: 10.1016/j.bbr.2008.01.012. Epub 2008 Feb 5.
Rats with unilateral lesion of the substantia nigra pars compacta (SNpc) have been used as a model of Parkinson's disease. Depending on the lesion protocol and on the drug challenge, these rats rotate in opposite directions. The aim of the present study was to propose a model to explain how critical factors determine the direction of these turns. Unilateral lesion of the SNpc was induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Separate analysis showed that neither the type of neurotoxin nor the site of lesion along the nigrostriatal pathway was able to predict the direction of the turns these rats made after they were challenged with apomorphine. However, the combination of these two factors determined the magnitude of the lesion estimated by tyrosine-hydroxylase immunohistochemistry and HPLC-ED measurement of striatal dopamine. Very small lesions did not cause turns, medium-size lesions caused ipsiversive turns, and large lesions caused contraversive turns. Large-size SNpc lesions resulted in an increased binding of [(3)H]raclopride to D2 receptors, while medium-size lesions reduced the binding of [(3)H]SCH-23390 D1 receptors in the ipsilateral striatum. These results are coherent with the model proposing that after challenged with a dopamine receptor agonist, unilaterally SNpc-lesioned rats rotate toward the side with the weaker activation of dopamine receptors. This activation is weaker on the lesioned side in animals with small SNpc lesions due to the loss of dopamine, but stronger in animals with large lesions due to dopamine receptor supersensitivity.
单侧黑质致密部（SNpc）损伤的大鼠已被用作帕金森病模型。根据损伤方案和药物激发情况，这些大鼠会向相反方向旋转。本研究的目的是提出一个模型，以解释关键因素如何决定这些旋转的方向。用6-羟基多巴胺（6-OHDA）或1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导SNpc单侧损伤。单独分析表明，无论是神经毒素的类型还是黑质纹状体通路沿线的损伤部位，都无法预测这些大鼠在接受阿扑吗啡激发后旋转的方向。然而，这两个因素的组合决定了通过酪氨酸羟化酶免疫组织化学和高效液相色谱-电化学检测纹状体多巴胺所估计的损伤程度。非常小的损伤不会导致旋转，中等大小的损伤会导致同侧旋转，而大的损伤会导致对侧旋转。大尺寸的SNpc损伤导致[³H]雷氯必利与D2受体的结合增加，而中等尺寸的损伤则降低了同侧纹状体中[³H]SCH-23390与D1受体的结合。这些结果与该模型一致该模型提出，在接受多巴胺受体激动剂激发后，单侧SNpc损伤的大鼠会向多巴胺受体激活较弱的一侧旋转。在SNpc损伤较小的动物中，由于多巴胺的丧失，损伤侧的这种激活较弱，但在损伤较大的动物中，由于多巴胺受体超敏反应，这种激活较强。
