Carta A R, Fenu S, Pala P, Tronci E, Morelli M
Department of Toxicology and Center of Excellence for Neurobiology of Addiction, University of Cagliari, 09124 Cagliari, Italy.
Eur J Neurosci. 2003 Nov;18(9):2563-72. doi: 10.1046/j.1460-9568.2003.02983.x.
The present study investigated long-term alterations in striatal gene expression after single exposure of unilaterally 6-hydroxydopamine-lesioned rats to different dopamine agonists (priming). Rats were primed with the D1 agonist SKF38393 (10 mg/kg), the D2/D3 agonist quinpirole (0.2 mg/kg), the dopamine precursor L-DOPA (50 mg/kg) or with vehicle (drug-naive), and GAD67, dynorphin and enkephalin mRNAs were evaluated in the striatum by in situ hybridization, 3 days after priming. To evaluate GAD67 mRNA in striatonigral and striatopallidal neurons, identified as enkephalin (-) and (+) neurons, double-labelling in situ hybridization was used. Drug-naive lesioned rats showed an increase in GAD67 mRNA in enkephalin (-) and (+) neurons, an increase in enkephalin and a decrease in dynorphin mRNAs. Priming with either SKF38393 or quinpirole further increased GAD67 mRNA in enkephalin (-) and (+) neurons, however, while SKF38393 produced a high and unbalanced activation toward enkephalin (-) neurons, after quinpirole the increase was of low intensity and similar in the two pathways. Dynorphin mRNA was increased by SKF38393 but not by quinpirole, whereas enkephalin mRNA was not changed by either priming. L-DOPA produced a high and similar increase in GAD67 mRNA in enkephalin (-) and (+) neurons. Priming differentially affected peptides and GAD67 mRNA in striatopallidal and striatonigral neurons depending on the dopamine agonist used. The degree of enduring overactivity of the striatopallidal and striatonigral pathways may be related to the ability of L-DOPA and D1 or D2/D3 receptor agonists to prime motor behavioural responses and to produce dyskinetic side-effects.
本研究调查了单侧6-羟基多巴胺损伤的大鼠单次暴露于不同多巴胺激动剂（启动）后纹状体基因表达的长期变化。大鼠分别用D1激动剂SKF38393（10mg/kg）、D2/D3激动剂喹吡罗（0.2mg/kg）、多巴胺前体L-多巴（50mg/kg）或溶剂（未用药）进行启动，启动3天后，通过原位杂交评估纹状体中谷氨酸脱羧酶67（GAD67）、强啡肽和脑啡肽的mRNA水平。为了评估被鉴定为脑啡肽（-）和（+）神经元的纹状体黑质和纹状体苍白球神经元中的GAD67 mRNA，采用了双标记原位杂交技术。未用药的损伤大鼠脑啡肽（-）和（+）神经元中的GAD67 mRNA增加，脑啡肽增加，强啡肽mRNA减少。用SKF38393或喹吡罗启动可进一步增加脑啡肽（-）和（+）神经元中的GAD67 mRNA，然而，SKF38393对脑啡肽（-）神经元产生高度且不均衡的激活，而喹吡罗启动后增加的强度较低且在两条通路中相似。SKF38393可增加强啡肽mRNA，但喹吡罗无此作用，而两种启动方式均未改变脑啡肽mRNA。L-多巴可使脑啡肽（-）和（+）神经元中的GAD67 mRNA产生高度且相似的增加。根据所使用的多巴胺激动剂不同，启动对纹状体苍白球和纹状体黑质神经元中的肽和GAD67 mRNA有不同影响。纹状体苍白球和纹状体黑质通路持久过度活跃的程度可能与L-多巴和D1或D2/D3受体激动剂引发运动行为反应及产生运动障碍副作用的能力有关。
