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：（改编自调查员的摘要）有机磷 杀虫剂（OPS）通过抑制施加毒性 乙酰胆碱酯酶，乙酰胆碱的积累和过量 刺激突触后胆碱能受体。 相当大的年龄有关 对这些药物的敏感性差异很明显。 我们假设这一点 抗胆碱酯酶毒性的突触前调节可以通过 乙酰胆碱的合成和/或释放的改变和/或 与年龄相关的敏感性差异是 由于相对，生物转化和突触后受体适应 这些突触前过程的活动或适应性。 急性灵敏度 对于当今使用的最常见的OP，将比较毒死 原型OP，PARATHION，新生儿，少年，年轻人和年龄大鼠。 与年龄相关的A-撒酯酶和羧酸酯酶成熟的差异 牛的排毒将与急性差异相关 灵敏度。 乙酰胆碱合成将通过测量来测定 高亲和力胆碱吸收，限速步骤。 调节作用 在不同年龄的高亲和力胆碱吸收上的体内暴露 将检查组并将其与其他神经化学的变化进行比较 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）或突触体研究 （烟碱自感受器），[3H]胆碱预载和钾诱发的 在超级发现系统中释放。 乙酰胆碱自身受体调节 将在不同年龄的OP暴露后释放离体释放 组并与急性OP灵敏度相关。 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 研究应定义相对活性和补偿性 成熟和衰老过程中突触前胆碱能机制并确定 它们调制对OP灵敏度的影响。