Male mice treated for 2 weeks with the anticholinesterase insecticide disulfoton (O,O-diethyl S-[2-(ethylthio)-ethyl] phosphorodithioate; 10 mg per kg per day) became tolerant to the hypothermic and antinociceptive effects of disulfoton itself and of oxotremorine, a muscarinic cholinergic agonist. Homogenates of brain and ileum from tolerant animals exhibited reduced binding of the specific muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB). In forebrains of tolerant animals, the number of receptors (Bmax) was decreased 40% with no change in the affinity constant. Acetylcholinesterase (AChE) activity was 15% of control. Forty-eight hours after a single injection of disulfoton (10 mg/kg) mice were more resistant than their controls to the hypothermic and antinociceptive effects of a second administration of the same insecticide and of oxotremorine. Tolerance was not present 96 hr after a single administration of disulfoton. A single injection of disulfoton produced 74, 65 and 27% inhibition of AChE activity after 4, 48 and 96 hr respectively. Four hours after a second injection at 49 and 96 hr, 73 or 72% inhibition was found. [3H]QNB binding of animals treated with a single injection of disulfoton and of controls did not differ at either time point. An increase in the Ki for inhibition of [3H]QNB binding by unlabeled oxotremorine was observed in forebrain from mice killed 48 hr after a single injection of disulfoton, indicating a decreased affinity of the muscarinic receptor for agonists. Binding of [3H]oxotremorine-M was decreased significantly 48 hr after a single injection of disulfoton and after chronic treatment. It is suggested that a differential down-regulation of muscarinic receptors occurs in acute and chronic tolerance, involving agonist and antagonist binding sites and depending on duration of exposure.

Differential alterations of cholinergic muscarinic receptors during chronic and acute tolerance to organophosphorus insecticides / Costa, L. G; Schwab, B. W; Murphy, S. D.. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 31:21(1982), p. 3407-13.

Differential alterations of cholinergic muscarinic receptors during chronic and acute tolerance to organophosphorus insecticides

Costa, L. G;
1982-01-01

Abstract

Male mice treated for 2 weeks with the anticholinesterase insecticide disulfoton (O,O-diethyl S-[2-(ethylthio)-ethyl] phosphorodithioate; 10 mg per kg per day) became tolerant to the hypothermic and antinociceptive effects of disulfoton itself and of oxotremorine, a muscarinic cholinergic agonist. Homogenates of brain and ileum from tolerant animals exhibited reduced binding of the specific muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB). In forebrains of tolerant animals, the number of receptors (Bmax) was decreased 40% with no change in the affinity constant. Acetylcholinesterase (AChE) activity was 15% of control. Forty-eight hours after a single injection of disulfoton (10 mg/kg) mice were more resistant than their controls to the hypothermic and antinociceptive effects of a second administration of the same insecticide and of oxotremorine. Tolerance was not present 96 hr after a single administration of disulfoton. A single injection of disulfoton produced 74, 65 and 27% inhibition of AChE activity after 4, 48 and 96 hr respectively. Four hours after a second injection at 49 and 96 hr, 73 or 72% inhibition was found. [3H]QNB binding of animals treated with a single injection of disulfoton and of controls did not differ at either time point. An increase in the Ki for inhibition of [3H]QNB binding by unlabeled oxotremorine was observed in forebrain from mice killed 48 hr after a single injection of disulfoton, indicating a decreased affinity of the muscarinic receptor for agonists. Binding of [3H]oxotremorine-M was decreased significantly 48 hr after a single injection of disulfoton and after chronic treatment. It is suggested that a differential down-regulation of muscarinic receptors occurs in acute and chronic tolerance, involving agonist and antagonist binding sites and depending on duration of exposure.
1982
Differential alterations of cholinergic muscarinic receptors during chronic and acute tolerance to organophosphorus insecticides / Costa, L. G; Schwab, B. W; Murphy, S. D.. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 31:21(1982), p. 3407-13.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2837050
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