BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF ACUTE CHLORPYRIFOS IN RATS - TOLERANCE TO PROLONGED INHIBITION OF CHOLINESTERASE

The preponderance of studies of tolerance to organophosphate (OP) chol inesterase (ChE) inhibitors indicates that functional recovery accompa nies neurochemical compensations for the inhibited enzyme. Contrary to prediction, rats dosed with the OP diisopropylfluorophosphate (DFP) s howed progressive and persistent impairment of cognitive and motor fun ction over a 3-week period of daily exposure, despite neurochemical an d pharmacological evidence of tolerance to its inhibition of ChE. To d etermine whether these functional effects of DFP resulted from inhibit ion of ChE and downregulation of muscarinic cholinergic receptors, rat s were dosed with chlorpyrifos (CPF), an OP pesticide which inhibits b lood and brain ChE of rats for weeks after a single injection. Long-Ev ans rats were trained to perform an appetitive test of memory and moto r function and were then injected s.c. with 0, 60, 125 or 250 mg/kg of CPF in peanut oil and tested 5 days/week for 7 weeks. Unconditioned b ehavior was also rated for signs of cholinergic toxicity. CPF inhibite d ChE activity in whole blood in a dose-related manner for more than 5 3 days. The degree and time course of ChE inhibition in blood and brai n and the downregulation of muscarinic receptors in brain after 125 mg /kg of CPF closely paralleled the previously reported effects of 25 da ily injections of 0.2 mg/kg of DFP. In addition, CPF-treated rats were subsensitive to oxotremorine-induced hypothermia for at least 32 days after CPF. However, functional deficits (in working memory and motor function) appeared within 2 days after injection of CPF and recovered within 3 weeks, long before ChE activity and receptor density returned to control levels. Thus, the effects of CPF were neither progressive nor as persistent as those seen during daily DFP injections. This diff erence suggests that the DFP-induced behavioral changes observed previ ously cannot be attributed entirely to its effects on ChE activity and changes in [H-3]quinuclidinyl benzilate binding.