The organophosphate, acetylcholinesterase inhibitor, disulfoton, O,O-diethyl S-[2-(ethylthio)ethyl]phosphorodithioate, was given daily for 2 weeks to male mice at two different dosages. Clinical signs of poisoning disappeared in 5 days after the beginning of the treatment, i.e., the animals developed apparent tolerance to disulfoton toxicity. Tolerant mice were less sensitive to a lethal dose of carbachol and exhibited a decrease of [3H]quinuclidinyl benzilate ([3H]QNB) binding in forebrain, hindbrain, and ileum. Scatchard analysis of saturation experiments revealed a decrease in the density of receptors (Bmax) in the disulfoton-treated mice, as compared with controls. No significant changes in affinity were found, except in the ileum. A time-course study showed a good parallelism between the decrease of [3H]QNB binding and the development of tolerance. Twenty-one days after the end of the disulfoton treatment AChE activity was still inhibited, but [3H]QNB binding had returned to normal levels. The recovery of [3H]QNB binding appears to be faster in ileum than in forebrain and hindbrain. These findings indicate that the development of tolerance to chronic organophosphate treatment is, at least partially, due to a reduction in the number of cholinergic receptors. © 1981.
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