Schwab B W, Hand H, Costa L G, Murphy S D
Neurotoxicology. 1981 Dec;2(4):635-47.
Tolerance to the toxic effects of exposure to the organophosphate acetylcholinesterase inhibitor, disulfoton, was induced by giving multiple, sublethal doses of the compound to male rats. Tolerance was judged to have been induced when toxic signs of exposure, including weight loss, were reversed or diminished. Binding of the specific muscarinic radioligand, [3H] quinuclidinyl benzilate ([3H] QNB) to ileal muscle, forebrain, and hindbrain from treated animals was significantly less than the amount bound to tissue from the control animals. Binding of [3H] QNB to heart tissue from tolerant animals was not different from control values. After a typical tolerance-inducing regimen of 7 doses of 2 mg/kg/day disulfoton followed by 4 doses of 3 mg/kg/day, [3H] QNB binding to heart from treated animals was 104% of controls, while binding to ileal muscle, forebrain, and hindbrain was 67, 69, and 77% of control values (p less than .001, .001 and .01), respectively. [3H] QNB binding was not decreased due to competition for binding sites with excess acetylcholine. Neither were decreases due to displacement by disulfoton, as an acute dose of disulfoton (which caused marked inhibition of acetylcholinesterase) did not result in decreased binding. The maximal binding (Bmax) to forebrain of tolerant animals was 56% of control (1.06 vs 1.88 pmol [3H] QNB mg protein-1, p less than 0.01), but no statistically significant change could be seen in equilibrium dissociation constants (Kd, 0.35 vs 0.36 nM). No changes in [3H] QNB binding constants occurred in hearts form tolerant animals. Differences between tolerant and control groups could be seen in [3H] QNB binding to striatum, but no alterations occurred in this brain area in the binding of dopaminergic or gabaergic radiolabels. The data presented in consistent with the hypothesis that cholinergic receptors are involved in organophosphate tolerance.
通过给雄性大鼠多次给予亚致死剂量的有机磷酸酯乙酰胆碱酯酶抑制剂乙拌磷，诱导其对乙拌磷暴露毒性作用产生耐受性。当包括体重减轻在内的暴露毒性迹象得到逆转或减轻时，判定诱导出了耐受性。特异性毒蕈碱放射性配体[³H]喹核醇基苯甲酸酯（[³H]QNB）与经处理动物的回肠肌、前脑和后脑的结合量显著低于与对照动物组织的结合量。[³H]QNB与耐受性动物心脏组织的结合与对照值无差异。在进行典型的诱导耐受性方案（7剂2mg/kg/天的乙拌磷，随后4剂3mg/kg/天）后，经处理动物心脏的[³H]QNB结合量为对照值的104%，而与回肠肌、前脑和后脑的结合量分别为对照值的67%、69%和77%（p分别小于0.001、0.001和0.01）。[³H]QNB结合量未因与过量乙酰胆碱竞争结合位点而降低。也不是由于乙拌磷的置换导致降低，因为急性剂量的乙拌磷（导致乙酰胆碱酯酶显著抑制）并未导致结合量降低。耐受性动物前脑的最大结合量（Bmax）为对照值的56%（1.06对1.88pmol[³H]QNB mg蛋白⁻¹，p小于0.01），但平衡解离常数（Kd，0.35对0.36nM）未见统计学显著变化。耐受性动物心脏的[³H]QNB结合常数未发生变化。耐受性组和对照组之间在[³H]QNB与纹状体的结合上存在差异，但该脑区多巴胺能或γ-氨基丁酸能放射性配体的结合未发生改变。所呈现的数据与胆碱能受体参与有机磷酸酯耐受性的假说一致。
