Janhunen Sanna, Mielikäinen Paula, Paldánius Päivi, Tuominen Raimo K, Ahtee Liisa, Kaakkola Seppo
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
Naunyn Schmiedebergs Arch Pharmacol. 2005 Jun;371(6):480-91. doi: 10.1007/s00210-005-1066-2. Epub 2005 Jul 13.
It is well established that nicotine activates brain dopaminergic systems and in addition has neuroprotective actions. Thus, nicotinic acetylcholine receptor (nAChR) agonists might be beneficial in the treatment of Parkinson's disease, and it is important to study the interactions of nicotine with drugs affecting the nigrostriatal dopaminergic pathway. We used brain microdialysis to study the effects of nicotine on extracellular levels of dopamine (DA) and its metabolites in the rat dorsal striatum in combination with drugs inhibiting either DA uptake (nomifensine), catechol-O-methyltransferase (COMT; tolcapone), monoamine oxidase B (MAO-B; selegiline) or DA receptors (haloperidol). Nicotine (0.5 mg/kg, s.c.) modestly increased DA output, and this effect was antagonised by mecamylamine but not by hexamethonium. Nomifensine (3 mg/kg, i.p.) substantially further enhanced the nicotine-induced increase in DA output and nomifensine+nicotine also evoked a strong mecamylamine-sensitive ipsilateral rotational behaviour in 6-hydroxydopamine lesioned rats. Tolcapone (10 mg/kg, i.p.) did not alter DA output, but markedly decreased homovanillic acid (HVA) and increased 3,4-dihydroxyphenylacetic acid (DOPAC). Selegiline pretreatment (5 x 1 mg/kg, i.p.) significantly increased extracellular DA and decreased DOPAC and HVA. Haloperidol (0.1 mg/kg, s.c.) slightly increased DA output and more clearly DOPAC and HVA. Tolcapone, selegiline or haloperidol did not enhance the nicotine-induced DA output. These results indicate that the activation of nigrostriatal nAChRs induces a significant DA release in the striatum, which is potentiated by DA uptake inhibition but not by COMT, MAO-B or presynaptic DA receptor inhibition. Our findings therefore agree with the notion that the termination of the effect of DA in the synapse mainly occurs via neuronal reuptake. Thus, selective nAChR agonists, possibly in combination with a DA uptake inhibitor, might improve dopaminergic transmission in Parkinson's disease.
众所周知，尼古丁可激活脑内多巴胺能系统，此外还具有神经保护作用。因此，烟碱型乙酰胆碱受体（nAChR）激动剂可能对帕金森病的治疗有益，研究尼古丁与影响黑质纹状体多巴胺能通路的药物之间的相互作用具有重要意义。我们使用脑微透析技术，结合抑制多巴胺摄取（诺米芬辛）、儿茶酚-O-甲基转移酶（COMT；托卡朋）、单胺氧化酶B（MAO-B；司来吉兰）或多巴胺受体（氟哌啶醇）的药物，研究尼古丁对大鼠背侧纹状体细胞外多巴胺（DA）及其代谢产物水平的影响。尼古丁（0.5mg/kg，皮下注射）适度增加了DA的释放量，这一效应被美加明拮抗，但未被六甲铵拮抗。诺米芬辛（3mg/kg，腹腔注射）显著进一步增强了尼古丁诱导的DA释放量增加，诺米芬辛+尼古丁还在6-羟基多巴胺损伤的大鼠中诱发了强烈的美加明敏感的同侧旋转行为。托卡朋（10mg/kg，腹腔注射）未改变DA的释放量，但显著降低了高香草酸（HVA）并增加了3,4-二羟基苯乙酸（DOPAC）。司来吉兰预处理（5×1mg/kg，腹腔注射）显著增加了细胞外DA并降低了DOPAC和HVA。氟哌啶醇（0.1mg/kg，皮下注射）轻微增加了DA的释放量，更明显地增加了DOPAC和HVA。托卡朋、司来吉兰或氟哌啶醇均未增强尼古丁诱导的DA释放量。这些结果表明，黑质纹状体nAChRs的激活在纹状体中诱导了显著的DA释放，多巴胺摄取抑制可增强这一作用，但COMT、MAO-B或突触前多巴胺受体抑制则不能。因此，我们的研究结果与多巴胺在突触中的作用主要通过神经元再摄取终止的观点一致。因此，选择性nAChR激动剂，可能与多巴胺摄取抑制剂联合使用，可能会改善帕金森病中的多巴胺能传递。
