Organophosphates (OPs) pose a constant threat to human health due to their widespread use as pesticides and their potential employment in military and terrorist attacks. The acute toxicity of OPs has been extensively studied; however, the consequences of prolonged or repeated exposure to levels of OPs that produce no overt signs of acute toxicity (i.e., subthreshold levels) are poorly understood. Further, there is clinical evidence that such repeated exposures to OPs lead to prolonged deficits in cognition, although the mechanism for this effect is unknown. In this study, the behavioral and neurochemical effects of repeated, intermittent, and subthreshold exposures to the alkyl OP, diisopropylfluorophosphate (DFP) were investigated. Rats were injected with DFP subcutaneously (dose range, 0.25-1.0 mg/kg) every other day over the course of 30 days, and then given a two week, DFP-free washout period. In behavioral experiments conducted at various times during the washout period, dose dependent decrements in a water maze hidden platform task and a spontaneous novel object recognition (NOR) procedure were observed, while prepulse inhibition of the acoustic startle response was unaffected. There were modest decreases in open field locomotor activity and grip strength (particularly during the DFP exposure period); however, rotarod performance and water maze swim speeds were not affected. After washout, DFP concentrations were minimal in plasma and brain, however, cholinesterase inhibition was still © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.Corresponding Author: Alvin V. Terry Jr., Ph.D., Professor of Pharmacology and Toxicology, CB-3618, Medical College of Georgia, 1120 Fifteenth Street, Augusta, Georgia 30912-2450, Phone 706-721-9462, Fax 706-721-2347.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Author ManuscriptNeuroscience. Author manuscript; available in PMC 2012 March 10.Published in final edited form as: Neuroscience. 2011 March 10; 176: 237-253. doi:10.1016/j.neuroscience.2010.031.
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript detectable in the brain. Moreover, the 1.0 mg/kg dose of DFP was associated with (brain regiondependent) alterations in nerve growth factor-related proteins and cholinergic markers. The results of this prospective animal study thus provide evidence to support two novel hypotheses: 1) that intermittent, subthreshold exposures to alkyl OPs can lead to protracted deficits in specific domains of cognition and 2) that such cognitive deficits may be related to persistent func...