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.