PRESYNAPTIC MODULATION OF ANTICHOLINESTERASE TOXICITY

抗胆碱酯酶毒性的突触前调节

• 批准号: 6178804
• 负责人: CAREY N POPE
• 金额: $ 24.5万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178804
• 关键词: acetylcholinesterase; age difference; animal old age; cholinergic receptors; cholinesterase inhibitors; cyclic AMP; dosage; environmental toxicology; laboratory rat; mature animal; neurotransmitter transport; newborn animals; organophosphorus insecticide; parathion; pesticide biological effect; receptor binding; tissue /cell culture; toxin metabolism

DESCRIPTION: (Adapted from the Investigator's Abstract) Organophosphorus insecticides (OPs) exert toxicity through inhibition of acetylcholinesterase, allowing accumulation of acetylcholine and excessive stimulation of postsynaptic cholinergic receptors. Considerable age-related differences in sensitivity to these agents are evident. We hypothesize that presynaptic modulation of anticholinesterase toxicity can occur through alterations in the synthesis and/or release of acetylcholine and that age-related differences in sensitivity are, along with differences in biotransformation and postsynaptic receptor adaptations, due to the relative activity or adaptability of these presynaptic processes. Acute sensitivity to the most common OP in use today, chlorpyrifos, will be compared to the prototype OP, parathion, in neonatal, juvenile, young adult and aged rats. Age-related differences in the A-esterase- and carboxylesterase-meditated detoxification of the oxons will be correlated with differences in acute sensitivity. Acetylcholine synthesis will be assayed by measuring high-affinity choline uptake, the rate-limiting step. Modulatory effects of in vivo OP exposure on high-affinity choline uptake in the different age groups will be examined and compared to changes in other neurochemical markers (acetylcholinesterase, muscarinic and nicotinic receptor binding). Acetylcholine release and its presynaptic autoreceptor-mediated modulation will be studied using brain slices (muscarinic autoreceptor) or synaptosomes (nicotinic autoreceptor), [3H]choline preloading and potassium-evoked release in a superfusion system. Autoreceptor regulation of acetylcholine release ex vivo following OP exposure will be compared in the different age groups and correlated with acute OP sensitivity. Finally, comparative age-related effects of OP exposures on the muscarinic receptor-mediated cAMP cascade and phosphoinositide turnover systems will be examined. These studies should define the relative activity and compensatory nature of presynaptic cholinergic mechanisms during maturation and aging and determine the effects of their modulation on OP sensitivity.

描述：（改编自研究者摘要）有机磷 杀虫剂（OP）通过抑制 乙酰胆碱酯酶，使乙酰胆碱和过量的积累 刺激突触后胆碱能受体。 相当大的年龄相关 对这些试剂的敏感性的差异是明显的。 我们假设 抗胆碱酯酶毒性的突触前调节可以通过 乙酰胆碱合成和/或释放的改变， 与年龄相关的敏感性差异，沿着 生物转化和突触后受体适应，由于相对 这些突触前过程的活动或适应性。 急性敏感性 到今天使用的最常见的OP，毒死蜱，将与 原型OP，在新生儿，幼年，年轻成年和老年大鼠。 A-酯酶和羧酸酯酶介导的与年龄相关的差异 oxons的解毒将与急性 灵敏度 乙酰胆碱合成将通过测量 高亲和力胆碱吸收，限速步骤。 的调制作用 OP暴露对不同年龄大鼠高亲和力胆碱摄取的影响 将对各组进行检查，并与其他神经化学物质的变化进行比较。 标记物（乙酰胆碱酯酶、毒蕈碱和烟碱受体结合）。 乙酰胆碱的释放及其突触前自身受体介导的调节 将使用脑切片（毒蕈碱自身受体）或突触体进行研究 （烟碱自身受体）、[3 H]胆碱预负荷和钾诱发的 在灌流系统中释放。 乙酰胆碱的自身受体调节 将在不同年龄段比较OP暴露后的体外释放 与急性OP敏感性相关。 最后，比较 OP暴露对毒蕈碱受体介导的cAMP的年龄相关影响 将检查级联和磷酸肌醇周转系统。 这些 研究应确定的相对活动和补偿性质， 突触前胆碱能机制在成熟和老化过程中， 它们的调制对OP灵敏度的影响。