Quik Maryka, Sum Jocelyn D, Whiteaker Paul, McCallum Sarah E, Marks Michael J, Musachio John, McIntosh J Michael, Collins Allan C, Grady Sharon R
The Parkinson's Institute, Sunnyvale, California 94089-1605, USA.
Mol Pharmacol. 2003 May;63(5):1169-79. doi: 10.1124/mol.63.5.1169.
Nigrostriatal damage leads to a reduction in striatal nicotinic acetylcholine receptors (nAChRs) in rodents, monkeys, and patients with Parkinson's disease. The present studies were undertaken to investigate whether these nAChR declines are associated with alterations in striatal nAChR function and, if so, to identify the receptor subtypes involved. To induce nigrostriatal damage, mice were injected with the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We measured [(125)I]3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid isopropyl ester (RTI-121, dopamine transporter), (125)I-alpha-conotoxin MII (putative alpha 6-containing sites in the central nervous system), (125)I-epibatidine (multiple sites), 5-[(125)I]iodo-3-[2(S)-azetidinylmethoxy]pyridine-2HCl ([(125)I]A85380; beta2-containing sites), and (125)I-alpha-bungarotoxin (alpha 7-containing sites) binding in brains from control and MPTP-treated mice, as well as nAChR function by [(3)H]dopamine release, [(3)H]GABA release, and [(86)Rb(+)] efflux. After MPTP treatment, declines were observed in striatal dopamine transporter levels, both binding and functional measures of striatal alpha-conotoxin MII-sensitive nAChRs, and selected measures of striatal alpha-conotoxin MII-resistant nAChRs. In contrast, (125)I-alpha-bungarotoxin binding sites were not altered after nigrostriatal damage. The changes in striatal nAChRs were selective, with no declines in cortex, thalamus, or septum. Those striatal binding and functional measures of nAChRs that decreased with MPTP treatment correlated with dopamine transporter declines, an observation suggesting that the binding and functional changes in nAChRs are limited to dopaminergic terminals. The present results are the first to demonstrate differential alterations in nAChR subtype function after nigrostriatal damage, with a close correspondence between changes in receptor binding sites and function. These data suggest that the declines in nAChR sites observed in Parkinson's disease brains may be of functional significance.
黑质纹状体损伤会导致啮齿动物、猴子以及帕金森病患者纹状体内烟碱型乙酰胆碱受体（nAChRs）减少。本研究旨在调查这些nAChR减少是否与纹状体nAChR功能改变有关，若有关，则确定涉及的受体亚型。为诱导黑质纹状体损伤，给小鼠注射选择性多巴胺能毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）。我们测量了对照组和MPTP处理组小鼠脑内的[(125)I]3β-(4-碘苯基)托烷-2β-羧酸异丙酯（RTI-121，多巴胺转运体）、(125)I-α-芋螺毒素MII（中枢神经系统中假定含α6的位点）、(125)I-埃博霉素（多个位点）、5-[(125)I]碘-3-[2(S)-氮杂环丁烷基甲氧基]吡啶-2HCl（[(125)I]A85380；含β2的位点）以及(125)I-α-银环蛇毒素（含α7的位点）的结合情况，还通过[(3)H]多巴胺释放、[(3)H]GABA释放和[(86)Rb(+)]外流测量了nAChR功能。MPTP处理后，纹状体多巴胺转运体水平下降，纹状体α-芋螺毒素MII敏感的nAChRs的结合和功能测量值下降，以及纹状体α-芋螺毒素MII耐药的nAChRs的选定测量值下降。相比之下，黑质纹状体损伤后(125)I-α-银环蛇毒素结合位点未改变。纹状体nAChRs的变化具有选择性，皮质、丘脑或隔区未见减少。那些随MPTP处理而减少的nAChRs的纹状体结合和功能测量值与多巴胺转运体下降相关，这一观察结果表明nAChRs的结合和功能变化仅限于多巴胺能终末。本研究结果首次证明黑质纹状体损伤后nAChR亚型功能存在差异改变，受体结合位点变化与功能密切对应。这些数据表明，在帕金森病脑内观察到的nAChR位点减少可能具有功能意义。
