Srinivasan J, Schmidt Werner J
Zoological institute, Neuropharmacology, University of Tuebingen, Auf der Morgenstelle 28E, 72076 Tuebingen, Germany.
Behav Brain Res. 2004 May 5;151(1-2):191-9. doi: 10.1016/j.bbr.2003.08.016.
In Parkinson's disease, besides the dopaminergic neurodegeneration, locus coeruleus noradrenergic neurons degenerate as well. Noradrenergic neurons have potential anti-parkinsonian, neuromodulatory and neuroprotective properties. Presently, an animal model with dopaminergic lesion has been used as a standard model of Parkinson's disease. The behavioral effects of dopaminergic agents in a Parkinson's animal model with additional noradrenergic lesions has not been studied so far. Here, the behavioral effects of dopaminergic agents L-DOPA (15 mg/kg) and D-amphetamine (4 mg/kg) in two different pathophysiological conditions have been explored; One group involving only dopaminergic deficiency with 6-hydroxydopamine (6-OHDA) and the other group with both dopaminergic and noradrenergic deficiency with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). DSP-4 specifically depleted noradrenaline from locus coeruleus terminal fields. 6-OHDA lesion depleted dopamine and its metabolites DOPAC, HVA and 3-MT in the regions of basal ganglia and it was potentiated by additional locus coeruleus denervation. Dopaminergic lesion produced catalepsy and hypoactivity. Hypoactivity in openfield was potentiated by additional noradrenergic denervation of locus coeruleus neurons. L-DOPA produced effective anticataleptic activity in group with both dopaminergic and noradrenergic lesions and D-amphetamine was found to be more effective in group only with dopaminergic lesions, indicating increased dopaminergic neurodegeneration after noradrenergic lesions. L-DOPA produced hyperactivity in dual neurodegenerated group indicating its differential activity in an animal model with noradrenergic and dopaminergic lesions. These findings indicate the neuroprotective and symptomatic role of noradrenergic neurons. It implicates the importance of noradrenergic pathophysiology in Parkinson's disease and its treatment and need for a more relevant animal model.
在帕金森病中，除了多巴胺能神经元变性外，蓝斑去甲肾上腺素能神经元也会发生变性。去甲肾上腺素能神经元具有潜在的抗帕金森病、神经调节和神经保护特性。目前，多巴胺能损伤的动物模型已被用作帕金森病的标准模型。到目前为止，尚未研究多巴胺能药物在具有额外去甲肾上腺素能损伤的帕金森病动物模型中的行为效应。在此，探讨了多巴胺能药物左旋多巴（15毫克/千克）和右旋苯丙胺（4毫克/千克）在两种不同病理生理条件下的行为效应；一组仅涉及用6-羟基多巴胺（6-OHDA）造成的多巴胺能缺乏，另一组涉及用N-(2-氯乙基)-N-乙基-2-溴苄胺（DSP-4）造成的多巴胺能和去甲肾上腺素能缺乏。DSP-4特异性地使蓝斑终末区域的去甲肾上腺素耗竭。6-OHDA损伤使基底神经节区域的多巴胺及其代谢产物3,4-二羟基苯乙酸（DOPAC）、高香草酸（HVA）和3-甲氧基酪胺（3-MT）耗竭，并且蓝斑额外去神经支配会使其加剧。多巴胺能损伤产生僵住症和活动减退。蓝斑神经元的额外去甲肾上腺素能去神经支配会增强旷场试验中的活动减退。左旋多巴在多巴胺能和去甲肾上腺素能均有损伤的组中产生有效的抗僵住症活性，并且发现右旋苯丙胺在仅具有多巴胺能损伤的组中更有效，表明去甲肾上腺素能损伤后多巴胺能神经元变性增加。左旋多巴在双重神经变性组中产生活动亢进，表明其在具有去甲肾上腺素能和多巴胺能损伤的动物模型中的不同活性。这些发现表明去甲肾上腺素能神经元的神经保护和症状性作用。这暗示了去甲肾上腺素能病理生理学在帕金森病及其治疗中的重要性以及需要更相关的动物模型。
