Department of Pharmacology, Universidade Federal do Paraná, Curitiba, PR, Brazil.
Neurotox Res. 2009 May;15(4):359-66. doi: 10.1007/s12640-009-9041-1. Epub 2009 Mar 18.
Nicotinic drugs have been proposed as putative drugs to treat Parkinson's disease (PD). In this study, we investigated whether nicotine can sensitize parkinsonian animals to the effect of dopaminergic drugs. Testing this hypothesis is important because nicotine has been shown to present neuroprotective and acute symptomatic effects on PD, but few studies have addressed the question of whether it may induce long-lasting effects on dopamine neurotransmission. We tested this hypothesis in the 6-hydroxydopamine (6-OHDA) rat model of PD. A pretreatment of these rats with 0.1-1.0 mg/kg nicotine induced a dose-dependent sensitization of the turning behavior when the animals were challenged with the dopamine receptor agonist apomorphine 24 h later. In agreement with previous studies, while apomorphine induced contraversive turns, nicotine, as well as amphetamine, induced ipsiversive turns in the 6-OHDA rats. This result suggests that, like amphetamine, nicotine induces turning behavior by promoting release of dopamine in the non-lesioned striatum of the rats. However, it is unlikely that the release of dopamine may also explain the nicotine-induced sensitization of turning behavior. First, the dopamine amount that could be released in the lesioned hemi-striatum by the nicotine pretreatment was minimum-less than 3%, as detected by HPLC-EC. Second, a pretreatment with amphetamine did not induce this behavioral sensitization. A pretreatment with apomorphine-induced sensitization, but it was minimal when compared to that induced by nicotine. Therefore, it is unlikely that the sensitization of the turning behavior induced by nicotine was consequent of the release of dopamine. However, the expression of such sensitization seems to depend on the activation of dopaminergic receptors, since it was seen when the nicotine-sensitized animals were challenged with apomorphine, but not with a second nicotine challenge. These findings are relevant for PD drug therapy since they suggest that the doses of dopaminergic drugs used to treat PD could be reduced if a nicotinic drug were co-administered.
烟碱类药物已被提议作为治疗帕金森病（PD）的潜在药物。在这项研究中，我们调查了尼古丁是否可以使帕金森病动物对多巴胺能药物的作用敏感。测试这一假设很重要，因为尼古丁已被证明对 PD 具有神经保护和急性症状作用，但很少有研究探讨它是否可能对多巴胺神经传递产生持久影响。我们在 6-羟多巴胺（6-OHDA）PD 大鼠模型中测试了这一假设。这些大鼠用 0.1-1.0mg/kg 尼古丁预处理后，24 小时后用多巴胺受体激动剂阿朴吗啡挑战时，会引起剂量依赖性的旋转行为敏感化。与先前的研究一致，阿朴吗啡诱导对侧旋转，而尼古丁和安非他命在 6-OHDA 大鼠中诱导同侧旋转。这一结果表明，与安非他命一样，尼古丁通过促进大鼠未损伤纹状体中多巴胺的释放来诱导旋转行为。然而，多巴胺的释放不太可能解释尼古丁诱导的旋转行为敏感化。首先，用尼古丁预处理可在损伤的半纹状体中释放的多巴胺量最小-少于 3%，如 HPLC-EC 检测到的。其次，安非他命预处理不会诱导这种行为敏感化。阿朴吗啡预处理诱导了这种敏感化，但与尼古丁诱导的敏感化相比，其程度较小。因此，尼古丁诱导的旋转行为敏感化不太可能是由于多巴胺的释放。然而，这种敏感化的表达似乎依赖于多巴胺能受体的激活，因为当尼古丁敏感的动物用阿朴吗啡而不是第二次尼古丁挑战时，会出现这种敏感化。这些发现与 PD 药物治疗有关，因为它们表明，如果联合使用烟碱类药物，用于治疗 PD 的多巴胺能药物的剂量可以减少。
