Bushnell P J, Pope C N, Padilla S
Neurotoxicology Division, United States Environmental Protection Agency, Research Triangle Park, North Carolina.
J Pharmacol Exp Ther. 1993 Aug;266(2):1007-17.
The preponderance of studies of tolerance to organophosphate (OP) cholinesterase (ChE) inhibitors indicates that functional recovery accompanies neurochemical compensations for the inhibited enzyme. Contrary to prediction, rats dosed with the OP diisopropylfluorophosphate (DFP) showed progressive and persistent impairment of cognitive and motor function over a 3-week period of daily exposure, despite neurochemical and pharmacological evidence of tolerance to its inhibition of ChE. To determine whether these functional effects of DFP resulted from inhibition of ChE and downregulation of muscarinic cholinergic receptors, rats were dosed with chlorpyrifos (CPF), an OP pesticide which inhibits blood and brain ChE of rats for weeks after a single injection. Long-Evans rats were trained to perform an appetitive test of memory and motor function and were then injected s.c. with 0, 60, 125 or 250 mg/kg of CPF in peanut oil and tested 5 days/week for 7 weeks. Unconditioned behavior was also rated for signs of cholinergic toxicity. CPF inhibited ChE activity in whole blood in a dose-related manner for more than 53 days. The degree and time course of ChE inhibition in blood and brain and the downregulation of muscarinic receptors in brain after 125 mg/kg of CPF closely paralleled the previously reported effects of 25 daily injections of 0.2 mg/kg of DFP. In addition, CPF-treated rats were subsensitive to oxotremorine-induced hypothermia for at least 32 days after CPF. However, functional deficits (in working memory and motor function) appeared within 2 days after injection of CPF and recovered within 3 weeks, long before ChE activity and receptor density returned to control levels. Thus, the effects of CPF were neither progressive nor as persistent as those seen during daily DFP injections. This difference suggests that the DFP-induced behavioral changes observed previously cannot be attributed entirely to its effects on ChE activity and changes in [3H]quinuclidinyl benzilate binding.
关于对有机磷酸酯（OP）胆碱酯酶（ChE）抑制剂耐受性的大多数研究表明，功能恢复伴随着对被抑制酶的神经化学补偿。与预测相反，每日暴露于OP二异丙基氟磷酸酯（DFP）的大鼠在3周的时间里，尽管有神经化学和药理学证据表明其对ChE抑制具有耐受性，但认知和运动功能仍出现渐进性和持续性损害。为了确定DFP的这些功能效应是否源于ChE抑制和毒蕈碱胆碱能受体的下调，给大鼠注射毒死蜱（CPF），这是一种OP农药，单次注射后数周内可抑制大鼠血液和脑中的ChE。将Long-Evans大鼠训练以进行记忆和运动功能的食欲测试，然后皮下注射0、60、125或250mg/kg的CPF于花生油中，并每周测试5天，共7周。还对非条件行为进行胆碱能毒性迹象的评分。CPF以剂量相关的方式抑制全血中的ChE活性超过53天。125mg/kg CPF给药后，血液和脑中ChE抑制的程度和时间进程以及脑中毒蕈碱受体的下调与先前报道的每日注射0.2mg/kg DFP 25次的效应密切平行。此外，CPF处理的大鼠在CPF后至少32天对氧化震颤素诱导的体温过低反应不敏感。然而，功能缺陷（工作记忆和运动功能方面）在注射CPF后2天内出现，并在3周内恢复，远早于ChE活性和受体密度恢复到对照水平。因此，CPF的效应既不是渐进性的，也不像每日注射DFP时那样持久。这种差异表明，先前观察到的DFP诱导的行为变化不能完全归因于其对ChE活性和[3H]喹核醇基苯甲酸酯结合变化的影响。
