Quik Maryka, Bordia Tanuja, Okihara Michaella, Fan Hong, Marks Michael J, McIntosh J Michael, Whiteaker Paul
The Parkinson's Institute, 1170 Morse Ave., Sunnyvale, CA 94089-1605, USA.
Mol Pharmacol. 2003 Sep;64(3):619-28. doi: 10.1124/mol.64.3.619.
Nicotinic acetylcholine receptor (nAChR) activation is well known to stimulate dopamine release in the striatum. This phenomenon may be physiologically significant in the control of motor function, as well as in pathological conditions such as Parkinson's disease. An understanding of the mechanisms that influence nAChR expression and function is therefore important. Because the dopamine precursor l-DOPA is the most commonly used therapeutic agent for Parkinson's disease, we investigated the effects of l-DOPA treatment on striatal nAChR expression in unlesioned and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In unlesioned animals, l-DOPA (15 mg/kg) administered twice daily for 2 weeks decreased both 125I-epibatidine and [125I]iodo-3-[2(S)-azetidinylmethoxy]pyridine (A-85380) binding sites in the caudate and putamen, but did not affect 125I-alpha-CtxMII sites. alpha-CtxMII inhibition of striatal 125I-epibatidine and [125I]A-85380 binding with alpha-CtxMII suggest that there are both high- (Ki < 0.2 nM) and low-affinity (Ki > 100 nM) alpha-CtxMII-sensitive sites, as well as alpha-CtxMII-resistant sites, and that l-DOPA treatment influences only the low-affinity alpha-CtxMII-sensitive subtype. The l-DOPA effect was selective for striatal nAChRs with no change in cortical sites. Monkeys with severe nigrostriatal damage did not exhibit l-DOPA-induced declines in striatal nAChRs, suggesting that l-DOPA primarily affects nAChRs associated with dopaminergic terminals. In summary, these data show that l-DOPA treatment decreases nAChR expression, in contrast with the well established up-regulation of these sites by chronic nicotine exposure. Furthermore, they demonstrate preferential l-DOPA regulation of a novel low-affinity alpha-CtxMII-sensitive site. These declines in nAChRs with l-DOPA may be relevant to both the therapeutic and side effect profiles of l-DOPA therapy in Parkinson's disease.
众所周知，烟碱型乙酰胆碱受体（nAChR）的激活会刺激纹状体中多巴胺的释放。这种现象在运动功能控制以及帕金森病等病理状况中可能具有重要的生理意义。因此，了解影响nAChR表达和功能的机制非常重要。由于多巴胺前体左旋多巴（l-DOPA）是帕金森病最常用的治疗药物，我们研究了l-DOPA治疗对未损伤和1-甲基-4-苯基-1,2,3,6-四氢吡啶损伤的猴子纹状体nAChR表达的影响。在未损伤的动物中，每天两次给予l-DOPA（15mg/kg），持续2周，可降低尾状核和壳核中125I-埃博霉素和[125I]碘-3-[2(S)-氮杂环丁烷甲氧基]吡啶（A-85380）的结合位点，但不影响125I-α-CTX MII位点。α-CTX MII对纹状体中125I-埃博霉素和[125I]A-85380结合的抑制作用表明，存在高亲和力（Ki<0.2nM）和低亲和力（Ki>100nM）的α-CTX MII敏感位点以及α-CTX MII抗性位点，并且l-DOPA治疗仅影响低亲和力的α-CTX MII敏感亚型。l-DOPA的作用对纹状体nAChR具有选择性，皮质位点无变化。患有严重黑质纹状体损伤的猴子未表现出l-DOPA诱导的纹状体nAChR下降，这表明l-DOPA主要影响与多巴胺能终末相关的nAChR。总之，这些数据表明，与长期尼古丁暴露使这些位点上调的情况相反，l-DOPA治疗会降低nAChR表达。此外，它们证明了l-DOPA对一种新型低亲和力α-CTX MII敏感位点的优先调节作用。l-DOPA导致的nAChR下降可能与帕金森病中l-DOPA治疗的治疗效果和副作用都相关。
