Differential alterations of cholinergic muscarinic receptors during chronic and acute tolerance to organophosphorus insecticides.
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.
D000110:Acetylcholinesterase / Q000378:metabolism; D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004222:Disulfoton / Q000494:pharmacology*; D004361:Drug Tolerance; D007082:Ileum / Q000378:metabolism; D007306:Insecticides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010095:Oxotremorine / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D000700:Analgesics; D007306:Insecticides; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D004222:Disulfoton; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate; D000110:Acetylcholinesterase