Lindner M D, Plone M A, Francis J M, Blaney T J, Salamone J D, Emerich D F
Cyto Therapeutics, Providence, RI 02906, USA.
Behav Brain Res. 1997 Jun;86(1):25-40. doi: 10.1016/s0166-4328(96)02240-1.
It is widely accepted that enduring parkinsonian symptoms are only evident if there are few remaining dopaminergic neurons in the substantia nigra and dopamine levels in the basal ganglia are very low [26,41]. In the present study, partial dopamine depletions were produced by infusing 6-OHDA bilaterally into the ventrolateral striatum as previously described [11,12,44]. Consistent with previous studies, behavioral deficits were detectable in rats with partial lesions with a simple fixed-ratio bar-pressing task. The present study demonstrated that these behavioral deficits were long-lasting, and that the sensitivity of this bar-pressing task could be increased by manipulating the level of difficulty of the task-higher fixed ratios were more sensitive to partial dopamine depletions. Deficits in rats with partial dopamine depletions could also be detected using non-automated neurological tests of parkinsonian symptoms developed for rats with severe unilateral dopamine depletions, but these deficits were transient and not as robust as those detected with the bar-pressing task. Oral Sinemet (L-DOPA:carbidopa) did not attenuate behavioral deficits related to partial dopamine depletions in this simple fixed-ratio bar-pressing task, but the present results suggest that Parkinson's patients might be identifiable earlier in the disease process, at a time when they could benefit from treatment with neuroprotective/neurotrophic agents. In addition, the results of the present study demonstrate that robust behavioral deficits may emerge with age. Mild dopamine depletions that were not detectable behaviorally at the time of the insult became clearly evident 10 months after the lesion with this bar-pressing task, and this may represent a more clinically relevant rodent model of Parkinson's disease.
人们普遍认为，只有当黑质中剩余的多巴胺能神经元很少且基底神经节中的多巴胺水平非常低时，才会出现持久的帕金森症状[26,41]。在本研究中，如先前所述[11,12,44]，通过双侧向腹外侧纹状体注入6-羟基多巴胺来产生部分多巴胺耗竭。与先前的研究一致，在具有部分损伤的大鼠中，通过简单的固定比率压杆任务可检测到行为缺陷。本研究表明，这些行为缺陷是持久的，并且通过操纵任务的难度水平可以提高这种压杆任务的敏感性——更高的固定比率对部分多巴胺耗竭更敏感。使用为严重单侧多巴胺耗竭的大鼠开发的帕金森症状的非自动化神经学测试，也可以检测到部分多巴胺耗竭大鼠的缺陷，但这些缺陷是短暂的，不如通过压杆任务检测到的缺陷那么明显。在这个简单的固定比率压杆任务中，口服息宁（左旋多巴：卡比多巴）并没有减轻与部分多巴胺耗竭相关的行为缺陷，但目前的结果表明，帕金森病患者可能在疾病过程的早期就可以被识别出来，此时他们可以从神经保护/神经营养药物治疗中受益。此外，本研究结果表明，随着年龄的增长可能会出现明显的行为缺陷。在损伤时行为上无法检测到的轻度多巴胺耗竭，在损伤后10个月通过这种压杆任务变得明显，这可能代表了一种更具临床相关性的帕金森病啮齿动物模型。
