Dyskinetic potential of dopamine agonists is associated with different striatonigral/striatopallidal zif-268 expression
Dyskinetic potential of dopamine agonists is associated with different striatonigral/striatopallidal zif-268 expression
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DOI：
10.1016/j.expneurol.2010.04.016
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发表时间：
2010-08-01
影响因子：
5.3
通讯作者：
Morelli, Micaela
中科院分区：
文献类型：
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作者：
Carta, Anna R.;Frau, Lucia;Morelli, Micaela
在多巴胺耗竭的纹状体中，传出神经元突触后信号的改变可能强调了对多巴胺能激动剂的可变动力障碍反应的发生。我们之前的研究表明，D1激动剂SKF-38393和D2激动剂罗匹尼罗在6-羟多巴胺损伤大鼠中分别诱导高强度和低强度的运动障碍反应。本研究评估了纹状体和纹状顶神经元中zif-268 mRNA的表达，以评估药物给药后这些不同运动障碍反应的神经化学标志物。急性和亚慢性SKF-38393 （3mg /kg）增加纹状体通路中每个神经元zif-268的表达，尽管亚慢性治疗减少了显示高早期基因水平的神经元数量。SKF-38393对纹状突起神经元Zif-268 mRNA表达无影响。相反，罗匹尼罗（5mg /kg）对纹状体神经元zif-268 mRNA无明显改变，而罗匹尼罗亚慢性地降低了zif-268 mRNA。急性和亚慢性罗匹尼罗均可降低纹状体通路中的zif-268水平。zif-268在纹状体和纹状顶神经元中的差异表达可能提供了SKF-38393和罗匹尼罗治疗所显示的运动障碍结果的生化相关性，这表明对药物给药后神经元反应的评估为行为测试之外的临床前运动障碍电位表征提供了一种工具。(C) 2010爱思唯尔公司版权所有。
In the dopamine-depleted striatum, an altered post-synaptic signalling of efferent neurons might underline the onset of variable dyskinetic responses to dopaminergic agonists. We have previously shown that a subchronic treatment with the D1 agonist SKF-38393 and the D2 agonist ropinirole induces a dyskinetic response of high and low intensities respectively, in 6-hydroxydopamine-lesioned rats. Here, zif-268 mRNA expression was evaluated in striatonigral and striatopallidal neurons to assess a neurochemical marker of these different dyskinetic responses upon drug administration. Acute and subchronic SKF-38393 (3 mg/kg) increased zif-268 expression per neuron in the striatonigral pathway, albeit the number of neurons displaying high early-gene levels was reduced by the subchronic treatment. Zif-268 mRNA in striatopallidal neurons was not affected by SKF-38393 treatments. In contrast, ropinirole (5 mg/kg) did not alter zif-268 mRNA in striatonigral neurons acutely, whereas ropinirole decreased zif-268 mRNA subchronically. Both acute and subchronic ropinirole decreased zif-268 levels in the striatopallidal pathway. The differential expression of zif-268 in striatonigral and striatopallidal neurons might provide a biochemical correlate of the dyskinetic outcome displayed by SKF-38393 and ropinirole treatments, suggesting that evaluation of neuronal responses upon drug administration provides a tool for the preclinical characterization of dyskinetic potential beyond behavioural tests. (C) 2010 Elsevier Inc. All rights reserved.