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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 4, 2007; DOI: 10.1124/jpet.107.125625

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Received for publication May 14, 2007.
Revised June 1, 2007.
Accepted for publication June 1, 2007.

Chronic, Intermittent Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

Alvin V. Terry, Jr. 1*, Debra A Gearhart 1, Wayne D Beck 1, Jacob N Truan 1, Mary Louise Middlemore 1, Leah N Williamson 2, Michael G Bartlett 2, Mark A Prendergast 3, Dale W Sickles 1, Jerry J Buccafusco 1

1 Medical College of Georgia 2 University of Georgia 3 University of Kentucky

* Address correspondence to: E-mail: aterry{at}mcg.edu

Abstract

Persistent behavioral abnormalities have been commonly associated with acute organophosphate (OP) pesticide poisoning; however, relatively little is known about the consequences of chronic OP exposures that are not associated with acute cholinergic symptoms. In this study, the behavioral and neurochemical effects of chronic, intermittent, and subthreshold exposures to the OP pesticide, chlorpyrifos (CPF) were investigated. Rat were injected with CPF subcutaneously (dose range, 2.5-18.0 mg/kg) every other day over the course of 30 days, and then given a two week, CPF-free washout period. In behavioral experiments conducted during the washout period, dose dependent decrements in a water maze hidden platform task and a prepulse inhibition procedure were observed, without significant effects on open field activity, rotorod performance, grip strength, or a spontaneous novel object recognition task. After washout, levels of CPF and its metabolite 3,5,6-trichloro-2-pyridinol (TCP) were minimal in plasma and brain, however, cholinesterase inhibition was still detectible. Further, the 18.0 mg/kg dose of CPF was associated with (brain region-dependent) decreases in nerve growth factor receptors and cholinergic proteins including the vesicular acetylcholine transporter, the high affinity choline transporter, and the {alpha}7 nicotinic acetylcholine receptor. These deficits were accompanied by decreases in anterograde and retrograde axonal transport measured in sciatic nerves ex vivo. Thus, low-level (intermittent) exposure to CPF has persistent effects on neurotrophin receptors and cholinergic proteins, possibly through inhibition of fast axonal transport. Such neurochemical changes may lead to deficits in information processing and cognitive function.


Key words: acetylcholine, cholinesterase, cognition, learning, nerve growth factor, organophosphate




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