PRESYNAPTIC MODULATION OF ANTICHOLINESTERASE TOXICITY

描述：(改编自《调查者摘要》)有机磷 杀虫剂(OPs)通过抑制 乙酰胆碱酯酶，允许乙酰胆碱积聚和过量 突触后胆碱能受体的刺激。相当大的年龄相关性 对这些药物的敏感性差异是显而易见的。我们假设 突触前调节抗胆碱酯酶毒性可通过 乙酰胆碱的合成和/或释放的变化 与年龄相关的敏感度差异以及 生物转化和突触后受体适应，由于相对的 这些突触前过程的活性或适应性。敏感度高 今天使用的最常见的有机磷，毒死蜱，将与 原型OP，对硫磷，在新生、幼年、青年和老年大鼠中使用。 A-酯酶和羧酸酯酶表达的年龄相关差异 毒素的解毒作用将与急性毒性的差异相关。 敏感度。乙酰胆碱的合成将通过测量进行检测 高亲和力胆碱摄取，限速步骤。的调制效应 活体OP暴露对不同年龄人群高亲和力胆碱摄取的影响 这些人将接受检查，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、毒鼠碱和烟碱受体结合)。 乙酰胆碱释放及其突触前自身受体介导的调制 将使用脑片(毒鼠碱自身受体)或突触体进行研究 (烟碱自身受体)、[~3H]胆碱预负荷和钾诱发 在灌流系统中释放。乙酰胆碱的自身受体调节 OP暴露后的体外释放将在不同年龄进行比较 并与急性OP敏感性相关。最后，比较 OP暴露对M受体介导的cAMP的增龄效应 将检查级联和磷脂酰肌醇周转系统。这些 研究应该定义相对活动和补偿性质 成熟衰老过程中突触前胆碱能机制的研究进展 它们的调制对OP灵敏度的影响。

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.