REDUCED MUSCARINIC RECEPTOR-BINDING IN TISSUES OF RATS TOLERANT TO THE INSECTICIDE DISULFOTON

  • 1 January 1981
    • journal article
    • research article
    • Vol. 2  (4) , 635-647
Abstract
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 controls. Binding of [3H]QNB to heart tissues from tolerant animals was not different from control values. After a typical tolerance-inducing regimen of 7 doses of 2 mg/kg per day disulfoton followed by 4 doses of 3 mg/kg per 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 < 0.001, 0.001 and 0.01), respectively. [3H]QNB binding was not decreased due to competition for binding sites with excess acetylcholine. Decreases were not 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, P < 0.01), but no statistically significant changes were seen in Kd, (0.35 vs. 0.36 nM). No changes in [3H]QNB binding constants occurred in hearts from tolerant animals. Differences between tolerant and control groups were seen in [3H]QNB binding to striatum, but no alterations occurred in this brain area in the binding of dopaminergic or GABAergic radiolabels. Data was consistent with the hypothesis that cholinergic receptors were involved in organophosphate tolerance.

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