Crofton K M, Reiter L W
Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
J Pharmacol Exp Ther. 1987 Dec;243(3):946-54.
Two behavioral tests, motor activity and the acoustic startle response (ASR), were used to test for dose-addition of cismethrin, a Type I, or deltamethrin, a Type II pyrethroid, with compounds active at the gamma-aminobutyric acid (GABAA) receptor complex (picrotoxin, muscimol and chlordiazepoxide). Additivity was assessed using a simplified version of isobolographic analysis using chlorpromazine and haloperidol as positive controls for dose-additivity. Dosage-effect functions for all compounds were determined for both motor activity and the ASR. The effects of various combinations of chlorpromazine (0.5-4.0 mg/kg) and haloperidol (0.05-0.2 mg/kg) on motor activity indicate dose-addition. To test for dose-addition of pyrethroids and GABAergic compounds, cismethrin (3-18 mg/kg) or deltamethrin (2-6 mg/kg) were administered 90 min before testing, either alone, or before treatment with picrotoxin (0.25-2.0 mg/kg), muscimol (0.6-2.5 mg/kg) or chlordiazepoxide (2.5-10 mg/kg) administered 20 to 30 min before testing. All compounds produced dosage-dependent decreases in motor activity. Muscimol and picrotoxin decreased ASR amplitude, increased ASR latency and reduced ASR sensitization to increasing background noise levels. Chlordiazepoxide had no effect on any measure of the ASR. Results from the interaction studies indicate dose-addition of the effects of picrotoxin and deltamethrin on motor activity and the ASR. Additivity of dose was not seen with any other combination. These data suggest that the in vivo effects of the Type II pyrethroid deltamethrin may be due in part to interaction with the picrotoxinin binding site of the GABAA receptor-ionophore complex. In addition, these results are consistent with reported differential effects of the two classes of pyrethroids on the GABAA receptor complex.
采用两项行为测试，即运动活性测试和声惊吓反应（ASR）测试，来检测顺式氯菊酯（一种I型拟除虫菊酯）或溴氰菊酯（一种II型拟除虫菊酯）与对γ-氨基丁酸（GABAA）受体复合物有活性的化合物（苦味毒、蝇蕈醇和氯氮卓）的剂量相加作用。使用等效应线分析的简化版本评估相加性，以氯丙嗪和氟哌啶醇作为剂量相加的阳性对照。测定了所有化合物对运动活性和ASR的剂量效应函数。氯丙嗪（0.5 - 4.0毫克/千克）和氟哌啶醇（0.05 - 0.2毫克/千克）的各种组合对运动活性的影响表明存在剂量相加作用。为了测试拟除虫菊酯和GABA能化合物的剂量相加作用，在测试前90分钟单独给予顺式氯菊酯（3 - 18毫克/千克）或溴氰菊酯（2 - 6毫克/千克），或者在测试前20至30分钟给予苦味毒（0.25 - 2.0毫克/千克）、蝇蕈醇（0.6 - 2.5毫克/千克）或氯氮卓（2.5 - 10毫克/千克）之前给予顺式氯菊酯或溴氰菊酯。所有化合物均使运动活性呈剂量依赖性降低。蝇蕈醇和苦味毒降低了ASR幅度，增加了ASR潜伏期，并降低了ASR对背景噪声水平增加的敏感性。氯氮卓对ASR的任何指标均无影响。相互作用研究的结果表明，苦味毒和溴氰菊酯对运动活性和ASR的作用存在剂量相加性。其他任何组合均未观察到剂量相加性。这些数据表明，II型拟除虫菊酯溴氰菊酯的体内效应可能部分归因于与GABAA受体 - 离子载体复合物的苦味毒结合位点相互作用。此外，这些结果与报道的两类拟除虫菊酯对GABAA受体复合物的不同作用一致。
