Cohn_1997_J.Pharmacol.Exp.Ther_283_312

Chlorpyrifos (CPF) is a cholinesterase-inhibiting organophosphate pesticide used extensively to treat crops and domestic animals. Two experiments determined the effects of acute and repeated CPF exposure on the acquisition and performance of response sequences. Adult male Long-Evans rats (n = 16), maintained at 300 g body weight were trained using food reinforcement under a multiple schedule of repeated acquisition (RA) and performance (P). The RA component required completion of a four-response sequence on three levers (e.g., center, right, left, right) that changed with each session, while the correct sequence in the P component was invariant. In experiment I, rats were orally administered vehicle (corn oil), 12.5, 25, 37.5 and 50 mg/kg CPF. Doses of 37.5 and 50 mg/kg produced greater accuracy decreases in RA than in P, suggesting a selective learning deficit. In experiment II, the rats were divided into two groups (n = 7), and received either vehicle or 12.5 mg/kg CPF, 5 day/wk, for 8 wk. Although 12.5 mg/kg CPF was barely effective when administered acutely, when administered repeatedly it initially decreased accuracy in both RA and P. Tolerance developed to CPF effects on P accuracy but not on RA accuracy. Microanalyses of response patterns indicated the most common type of error was a progression through the sequence as if incorrect responses were actually correct. Radiometric analyses of serum cholinesterase activity showed CPF produced 90% inhibition at 3 hr and 85% inhibition at 24 hr postexposure. These results show that both acute and repeated CPF produced a selective deficit in the learning of response sequences in rats. This selectivity was most clearly expressed through the development of tolerance to the disruptive effects of repeated CPF on the performance but not the learning of response sequences.