Lim D K, Hoskins B, Ho I K
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Toxicol Appl Pharmacol. 1987 Sep 30;90(3):465-76. doi: 10.1016/0041-008x(87)90139-6.
Rats were treated with diisopropylfluorophosphate (DFP) acutely or daily for 14 days. The involvement of various presynaptic and postsynaptic functions of the cholinergic system in the development of tolerance to DFP was studied. Receptor density and affinity of both muscarinic and nicotinic receptors, high-affinity choline uptake, and [K+]-evoked release of acetylcholine (ACh) by atropine were not changed after acute administration of 2 mg/kg DFP. Both muscarinic and nicotinic receptors were down-regulated to the same extent (40-50%) after subacute administration of DFP (1 mg/kg) without changes in their affinities. Binding sites of muscarinic receptors were maximally decreased after 7 days of DFP administration. Thereafter, they remained constant throughout 14 days of administration. One hour after the last injection of 2 mg/kg DFP to subacutely treated rats, the maximum velocity of high-affinity choline uptake was significantly decreased in the striatum (33%) and hippocampus (53%) without changes in Km values. Twenty-four hours after the last injection of DFP, only a higher dose of DFP (2 mg/kg) significantly inhibited choline uptake. Potassium-evoked release of ACh by slices of striatum was not different between acutely and subacutely treated rats. However, the release of ACh by slices of striatum and hippocampus was significantly increased by atropine in subacutely treated rats. It is suggested that along with the down-regulation of the postsynaptic receptors, subsensitivity of presynaptic functions of the cholinergic synapse also develops during subacute administration of DFP.
大鼠被急性给予二异丙基氟磷酸酯（DFP）或每日给予DFP，持续14天。研究了胆碱能系统各种突触前和突触后功能在对DFP耐受性发展中的作用。急性给予2mg/kg DFP后，毒蕈碱型和烟碱型受体的受体密度和亲和力、高亲和力胆碱摄取以及阿托品诱发的[K⁺]依赖性乙酰胆碱（ACh）释放均未改变。亚急性给予DFP（1mg/kg）后，毒蕈碱型和烟碱型受体均下调至相同程度（40 - 50%），但其亲和力未改变。给予DFP 7天后，毒蕈碱型受体的结合位点最大程度降低。此后，在整个14天给药期间保持不变。对亚急性处理的大鼠最后一次注射2mg/kg DFP 1小时后，纹状体（33%）和海马体（53%）中高亲和力胆碱摄取的最大速度显著降低，而Km值未改变。最后一次注射DFP 24小时后，只有较高剂量的DFP（2mg/kg）显著抑制胆碱摄取。急性和亚急性处理的大鼠纹状体切片中钾诱发的ACh释放没有差异。然而，在亚急性处理的大鼠中，阿托品可显著增加纹状体和海马体切片中ACh的释放。提示在亚急性给予DFP期间，除了突触后受体下调外，胆碱能突触的突触前功能也会出现亚敏感性。
