Repeated inhibition of cholinesterase by chlorpyrifos in rats: behavioral, neurochemical and pharmacological indices of tolerance.
Previous work from this laboratory showed that daily s.c. injections of the organophosphate diisopropylfluorophosphate caused prolonged inhibition of cholinesterase (ChE) activity in whole blood and brain and downregulation of muscarinic receptors in the central nervous system; these changes were accompanied by progressive, persistent deterioration of working memory and motor function. Further, a single s.c. injection of the organophosphate insecticide chlorpyrifos (O,O',-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), caused neurochemical changes of the same magnitude and duration, but transient impairment of working memory and motor slowing. In the present study, weekly injections of CPF (0, 15, 30 or 60 mg/kg s.c.) inhibited ChE activity in whole blood of rats by 60% to 90% after 5 weeks; the highest dose also induced tremor, working memory impairment and motor slowing in daily delayed matching-to-position/visual discrimination tests. Reducing the CPF injection frequency to every other week relieved the inhibition of whole blood ChE activity (to 50%-75% of control) and ameliorated all the behavioral deficits. Reinstatement of weekly CPF injections (0, 15, 30, or 45 mg/kg) for 10 weeks inhibited whole blood ChE activity by 75% to 90%. Tremor was not observed during this period; however, motor slowing and working memory impairment persisted throughout the dosing period in all treated groups. Pharmacological evidence for tolerance to the muscarinic effects of CPF was observed on trial completion in the daily delayed matching-to-position/visual discrimination task: CPF-treated rats were supersensitive to scopolamine and subsensitive to pilocarpine. Nicotine reversed the reduction in trial completion associated with CPF. Changes in sensitivity to mecamylamine, d-amphetamine and haloperidol were not observed. Taken together, these studies indicate that inhibition of ChE activity by repeated injection of CPF produces a constellation of behavioral effects not evident after a single CPF treatment, even though both treatment regimens caused prolonged inhibition of ChE activity and downregulation of central muscarinic receptors.
Bushnell
P J
PJ
Neurotoxicology Division, Health Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina.
Kelly
K L
KL
Ward
T R
TR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004390:Chlorpyrifos / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000097:blood; D003214:Conditioning, Classical / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance; D008297:Male; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D010095:Oxotremorine / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014316:Tritium; D014796:Visual Perception / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D011976:Receptors, Muscarinic; D014316:Tritium; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate; D002802:Cholinesterases; D004390:Chlorpyrifos