Presynaptic involvement in the nicotine prevention of the dopamine loss provoked by 6-OHDA administration in the substantia nigra
Presynaptic involvement in the nicotine prevention of the dopamine loss provoked by 6-OHDA administration in the substantia nigra
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DOI：
10.1080/10298420290015863
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发表时间：
2002-01-01
影响因子：
3.7
通讯作者：
Dajas, Federico
中科院分区：
文献类型：
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作者：
Andres Abin-Carriquiry, J.;McGregor-Armas, Ronald;Dajas, Federico
虽然尼古丁通过刺激特定亚群的烟碱型乙酰胆碱受体(NAChR)似乎可以保护培养的细胞免受各种侮辱，但体内研究显示出有争议的结果。在前文中我们已经证明，在6-羟基多巴胺(6-OHDA)实验性帕金森病模型中，间歇给予尼古丁(6-OHDA前4h，6-OHDA后20、44和68h)可防止黑质部分损伤(6-OHDA 6 mU g后神经元死亡50%)引起的纹状体(CS)多巴胺(DA)浓度下降。为了进一步分析尼古丁效应的机制，我们利用尼古丁给药程序对纹状体细胞外DA浓度进行了微透析研究，该程序能够防止DA减少。6-OHDA作用后，CS细胞外基础DA浓度维持不变，且不受尼古丁的影响。神经毒性给药后基础DOPAC水平下降。细胞外DA对氯化钾(KCl)刺激的反应在6-OHDA后明显低于对照组。尼古丁显著逆转了这一下降趋势。以前的研究表明，在6-OHDA毒性作用下存活下来的纹状体DA终末能够将细胞外DA浓度保持在接近正常水平，可能会增加DA的合成。然而，应用释放因子，如KCl，显示了这种平衡的脆弱性，暴露了末端数量的减少。尼古丁通过进一步激活酪氨酸羟化酶和DA合成，或通过延长DA终末的寿命，可以逆转6-OHDA的作用。
While nicotine, through stimulation of a specific sub population of nicotinic acetylcholine receptors (nAChR) appears to protect cells in culture against a variety of insults, studies in vivo show controversial results. In a previous paper we have shown that in the 6-hydroxydopamine (6-OHDA) model of experimental parkinsonism, an intermittent administration schedule of nicotine (4h before and 20, 44 and 68h after 6-OHDA) was able to prevent the decrease of dopamine (DA) concentration in the corpus striatum (CS) provoked by the partial lesion of the substantia nigra (50% neuronal death after 6 mu g of 6-OHDA). To further analyze the mechanisms of nicotine effects, we performed a microdialysis study of striatal extracellular DA concentrations utilizing the nicotine administration schedule that was able to prevent DA decrease. Basal extracellular DA concentrations in the CS were maintained after 6-OHDA and were not modified by nicotine. Basal DOPAC levels were decreased after the neurotoxic administration. The response of extracellular DA to potassium chloride (KCl) challenge was significantly lower after 6-OHDA than in control animals. Nicotine significantly reversed this decrease. As previous studies have shown, the striatal DA terminals surviving the 6-OHDA toxic effect are able to keep extracellular DA concentrations close to normal, likely increasing DA synthesis. Nevertheless, the application of a releasing factor such as KCl shows the fragility of this equilibrium, exposing a decrease in the terminal number. Nicotine, through a further activation of tyrosine hydroxylase and DA synthesis or by prolonging the life of DA terminals, could reverse the effect of 6-OHDA.