Chronic organophosphorus exposure and cognition

Abstract

Abstract : Chronic, low-level exposure to acetylcholinesterase (AChE) inhibitor organophosphorus (OP) insecticides or chemical warfare agents produces abnormalities in the function of brain acetylcholine (ACh) neurons, and in humans they may be associated with impaired cognitive function well after withdrawal from such exposure. The purpose of the present study was to identify the severity of cognitive impairment of rats and monkeys following protracted withdrawal from chronic, Low-level exposure to the OP agent diisopropylfluorophosphate (DFP). Assessment of spatial learning (water maze task) in rats began 1 - 17 days after completion of either a 14 day once daily DFP (50,250, or 500 microngram/kg) or vehicle treatment regimen. During the 14 day regimen, prior to withdrawal, spontaneous activity and olfactory behaviors were initially suppressed during DFP exposure, effects to which the subjects became tolerant after receiving the (250 microngram/kg dose) regimen. Performance of the spatial memory task was impaired for up to 21 days after withdrawal from the standard DFP regimen. DFP failed to impair the acquisition of the spatial memory task in rats who had previously experienced the task. Performance of a previously we 11- learned delayed matching task by monkeys was not affected by DFP regimens after withdrawal of the drug. These results in monkeys also complement those showing that the DFP regimen did not alter the performance of rats working a previously well- learned delayed discrimination task. The DFP regimen induced a protracted decrease in the expression of nicotinic and muscarinic (M2) receptors in several brain regions. However, in certain regions of the hippocampus (e.g., CA1 or subiculum) the decreased expression of nicotinic receptors was still evident 3 weeks after withdrawal from DFP. Levels of AChE activity also were slower to recover for this brain region. This decreased rate of enzyme and cholinergic receptor recovery may underlie