O'Leary Kathryn T, Parameswaran Neeraja, Johnston Louisa C, McIntosh J Michael, Di Monte Donato A, Quik Maryka
The Parkinson's Institute, 675 Almanor Ave., Sunnyvale, CA 94085-2934, USA.
J Pharmacol Exp Ther. 2008 Oct;327(1):124-9. doi: 10.1124/jpet.108.141861. Epub 2008 Jul 7.
Paraquat, an herbicide widely used in the agricultural industry, has been associated with lung, liver, and kidney toxicity in humans. In addition, it is linked to an increased risk of Parkinson's disease. For this reason, we had previously investigated the effects of paraquat in mice and showed that it influenced striatal nicotinic receptor (nAChR) expression but not nAChR-mediated dopaminergic function. Because nonhuman primates are evolutionarily closer to humans and may better model the effects of pesticide exposure in man, we examined the effects of paraquat on striatal nAChR function and expression in monkeys. Monkeys were administered saline or paraquat once weekly for 6 weeks, after which nAChR levels and receptor-evoked [(3)H]dopamine ([(3)H]DA) release were measured in the striatum. The functional studies showed that paraquat exposure attenuated dopamine (DA) release evoked by alpha3/alpha6beta2() (nAChR that is composed of the alpha3 or alpha6 subunits, and beta2; the asterisk indicates the possible presence of additional subunits) nAChRs, a subtype present only on striatal dopaminergic terminals, with no decline in release mediated by alpha4beta2() (nAChR containing alpha4 and beta2 subunits, but not alpha3 or alpha6) nAChRs, present on both DA terminals and striatal neurons. Paraquat treatment decreased alpha4beta2() but not alpha3/alpha6beta2() nAChR expression. The differential effects of paraquat on nAChR expression and receptor-evoked [(3)H]DA release emphasize the importance of evaluating changes in functional measures. The finding that paraquat treatment has a negative impact on striatal nAChR-mediated dopaminergic activity in monkeys but not mice indicates the need for determining the effects of pesticides in higher species.
百草枯是一种在农业行业广泛使用的除草剂，与人类的肺、肝和肾毒性有关。此外，它还与帕金森病风险增加有关。因此，我们之前研究了百草枯对小鼠的影响，结果表明它会影响纹状体烟碱型受体（nAChR）的表达，但不影响nAChR介导的多巴胺能功能。由于非人类灵长类动物在进化上与人类更接近，可能能更好地模拟农药暴露对人类的影响，我们研究了百草枯对猴子纹状体nAChR功能和表达的影响。猴子每周接受一次生理盐水或百草枯注射，持续6周，之后测量纹状体中nAChR水平和受体诱发的[³H]多巴胺（[³H]DA）释放。功能研究表明，百草枯暴露减弱了由α3/α6β2*（由α3或α6亚基以及β2组成的nAChR；星号表示可能存在其他亚基）nAChRs诱发的多巴胺（DA）释放，α3/α6β2是仅存在于纹状体多巴胺能终末的一种亚型，而由α4β2（包含α4和β2亚基，但不包含α3或α6的nAChR）nAChRs介导的释放没有下降，α4β2存在于多巴胺能终末和纹状体神经元上。百草枯处理降低了α4β2但没有降低α3/α6β2* nAChR的表达。百草枯对nAChR表达和受体诱发的[³H]DA释放的不同影响强调了评估功能指标变化的重要性。百草枯处理对猴子纹状体nAChR介导的多巴胺能活性有负面影响，但对小鼠没有影响，这一发现表明有必要确定农药对高等物种的影响。
