REPEATED INHIBITION OF CHOLINESTERASE BY CHLORPYRIFOS IN RATS - BEHAVIORAL, NEUROCHEMICAL AND PHARMACOLOGICAL INDEXES OF TOLERANCE

Previous work from this laboratory showed that daily s.c. injections o f the organophosphate diisopropylfluorophosphate caused prolonged inhi bition of cholinesterase (ChE) activity in whole blood and brain and d ownregulation of muscarinic receptors in the central nervous system; t hese changes were accompanied by progressive, persistent deterioration of working memory and motor function. Further, a single s.c. injectio n of the organophosphate insecticide chlorpyrifos (O,O',-diethyl O-3,5 ,6-trichloro-2-pyridyl phosphorothionate, CPF), caused neurochemical c hanges of the same magnitude and duration, but transient impairment of working memory and motor slowing. In the present study, weekly inject ions of CPF (0, 15, 30 or 60 mg/kg s.c.) inhibited ChE activity in who le blood of rats by 60% to 90% after 5 weeks; the highest dose also in duced tremor, working memory impairment and motor slowing in daily del ayed matching-to-position/visual discrimination tests. Reducing the CP F injection frequency to every other week relieved the inhibition of w hole blood ChE activity (to 50%-75% of control) and ameliorated all th e 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 s lowing and working memory impairment persisted throughout the dosing p eriod 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-tr eated rats were supersensitive to scopolamine and subsensitive to pilo carpine. Nicotine reversed the reduction in trial completion associate d 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 t reatment, even though both treatment regimens caused prolonged inhibit ion of ChE activity and downregulation of central muscarinic receptors .