Bushnell P J, Kelly K L, Ward T R
Neurotoxicology Division, Health Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina.
J Pharmacol Exp Ther. 1994 Jul;270(1):15-25.
Previous work from this laboratory showed that daily s.c. injections of the organophosphate diisopropylfluorophosphate caused prolonged inhibition of cholinesterase (ChE) activity in whole blood and brain and downregulation of muscarinic receptors in the central nervous system; these changes were accompanied by progressive, persistent deterioration of working memory and motor function. Further, a single s.c. injection of the organophosphate insecticide chlorpyrifos (O,O',-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), caused neurochemical changes of the same magnitude and duration, but transient impairment of working memory and motor slowing. In the present study, weekly injections of CPF (0, 15, 30 or 60 mg/kg s.c.) inhibited ChE activity in whole blood of rats by 60% to 90% after 5 weeks; the highest dose also induced tremor, working memory impairment and motor slowing in daily delayed matching-to-position/visual discrimination tests. Reducing the CPF injection frequency to every other week relieved the inhibition of whole blood ChE activity (to 50%-75% of control) and ameliorated all the behavioral deficits. Reinstatement of weekly CPF injections (0, 15, 30, or 45 mg/kg) for 10 weeks inhibited whole blood ChE activity by 75% to 90%. Tremor was not observed during this period; however, motor slowing and working memory impairment persisted throughout the dosing period in all treated groups. Pharmacological evidence for tolerance to the muscarinic effects of CPF was observed on trial completion in the daily delayed matching-to-position/visual discrimination task: CPF-treated rats were supersensitive to scopolamine and subsensitive to pilocarpine. Nicotine reversed the reduction in trial completion associated with CPF. Changes in sensitivity to mecamylamine, d-amphetamine and haloperidol were not observed. Taken together, these studies indicate that inhibition of ChE activity by repeated injection of CPF produces a constellation of behavioral effects not evident after a single CPF treatment, even though both treatment regimens caused prolonged inhibition of ChE activity and downregulation of central muscarinic receptors.
该实验室之前的研究表明，每日皮下注射有机磷酸酯二异丙基氟磷酸酯会导致全血和大脑中胆碱酯酶（ChE）活性长期受到抑制，以及中枢神经系统中毒蕈碱受体下调；这些变化伴随着工作记忆和运动功能的渐进性、持续性衰退。此外，单次皮下注射有机磷酸酯杀虫剂毒死蜱（O,O'-二乙基-O-3,5,6-三氯-2-吡啶基硫代磷酸酯，CPF）会引起同等程度和持续时间的神经化学变化，但会导致工作记忆短暂受损和运动迟缓。在本研究中，每周注射CPF（0、15、30或60毫克/千克，皮下注射）5周后，大鼠全血中的ChE活性被抑制了60%至90%；最高剂量还在每日延迟位置匹配/视觉辨别测试中诱发了震颤、工作记忆损害和运动迟缓。将CPF注射频率降低至每隔一周可减轻对全血ChE活性的抑制（降至对照组的50%-75%），并改善所有行为缺陷。恢复每周注射CPF（0、15、30或45毫克/千克）10周，可使全血ChE活性受到75%至90%的抑制。在此期间未观察到震颤；然而，在整个给药期间，所有治疗组均持续存在运动迟缓和工作记忆损害。在每日延迟位置匹配/视觉辨别任务完成时，观察到对CPF毒蕈碱样作用产生耐受性的药理学证据：CPF处理的大鼠对东莨菪碱超敏，对毛果芸香碱低敏。尼古丁逆转了与CPF相关的试验完成率降低。未观察到对美加明、右旋苯丙胺和氟哌啶醇敏感性的变化。综上所述，这些研究表明，即使两种治疗方案均导致ChE活性长期受到抑制和中枢毒蕈碱受体下调，但重复注射CPF抑制ChE活性会产生一系列单次CPF治疗后未出现的行为效应。
