CHRONIC, LOW-LEVEL EXPOSURE TO DIISOPROPYLFLUOROPHOSPHATE CAUSES PROTRACTED IMPAIRMENT OF SPATIAL NAVIGATION LEARNING

Chronic, low-level exposure to cholinesterase inhibitor organophosphat e (OF) insecticides or chemical warfare agents produces abnormalities in CNS acetylcholine (ACh) function, and in humans, may be associated with impaired cognitive function well after withdrawal from such expos ure. The purpose of the present study was to identify the severity of impairment in spatial learning of rats following protracted withdrawal from chronic, low-level exposure to the OP agent diisopropylfluoropho sphate (DFP). Assessment of spatial learning began either 3 or 17 days after completion of a 14-day DFP treatment regimen (50, 250, or 500 m u g/kg). During the 14-day treatment regimen, spontaneous activity and olfactory behaviors were suppressed, effects which subsided with repe ated exposure to the 250 mu g/kg dose regimen. In contrast, both behav iors were stimulated by exposure to the 50 mu g/kg dose regimen, as wa s body weight gain. Performance of the spatial test of working memory was impaired for up to 21 days after withdrawal from treatment with a 250 mu g/kg dose of DFP. AChE activity in the frontal cortex and hippo campus was suppressed to 42.58% and 50.35% of control levels, respecti vely, 3 days after completion of the DFP (250 mu g/kg) treatment regim en. By 7 days after withdrawal from treatment, AChE activity in the co rtex and hippocampus had recovered to 81.87% and 64.61% of control lev els, respectively. These levels represent increases in activity of 39. 29% and 14.26% in these regions, as compared to AChE activity 3 days a fter DFP withdrawal. By 21 days after withdrawal from treatment, AChE in both brain regions had recovered to levels similar to those of cont rols. Chronic, low-level OP exposure, therefore, produces protracted i mpairment of working memory after drug withdrawal that is not associat ed with continued suppression of AChE activity. This impairment may, h owever, be associated with a decreased rate of AChE recovery in the hi ppocampus, relative to the cortex. This decreased rate of enzyme recov ery may contribute to hippocampal toxicity underlying protracted impai rment of working memory.