Repeated, intermittent exposures to diisopropylfluorophosphate in rats

Protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function

Alvin V Terry, J. J. Buccafusco, D. A. Gearhart, W. D. Beck, M. L. Middlemore-Risher, J. N. Truan, G. M. Schwarz, M. Xu, M. G. Bartlett, A. Kutiyanawala, Anilkumar R Pillai

Research output: Contribution to journalArticle

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Abstract

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 s.c. (dose range, 0.25-1.0 mg/kg) every other day over the course of 30 days, and then given a 2 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 detectable in the brain. Moreover, the 1.0 mg/kg dose of DFP was associated with (brain region-dependent) 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 functional changes in brain neurotrophin and cholinergic pathways.

Original languageEnglish (US)
Pages (from-to)237-253
Number of pages17
JournalNeuroscience
Volume176
DOIs
StatePublished - Mar 10 2011

Fingerprint

Isoflurophate
Organophosphates
Nerve Growth Factor
Cognition
Cholinergic Agents
Proteins
Brain
Startle Reflex
Water
Cholinesterases
Nerve Growth Factors
Hand Strength
Locomotion
Pesticides
Acoustics
Prospective Studies
Health

Keywords

  • Acetylcholine
  • Cognition
  • Memory
  • Nerve agent
  • Neurotrophin
  • Organophosphate

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Repeated, intermittent exposures to diisopropylfluorophosphate in rats : Protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function. / Terry, Alvin V; Buccafusco, J. J.; Gearhart, D. A.; Beck, W. D.; Middlemore-Risher, M. L.; Truan, J. N.; Schwarz, G. M.; Xu, M.; Bartlett, M. G.; Kutiyanawala, A.; Pillai, Anilkumar R.

In: Neuroscience, Vol. 176, 10.03.2011, p. 237-253.

Research output: Contribution to journalArticle

Terry, Alvin V ; Buccafusco, J. J. ; Gearhart, D. A. ; Beck, W. D. ; Middlemore-Risher, M. L. ; Truan, J. N. ; Schwarz, G. M. ; Xu, M. ; Bartlett, M. G. ; Kutiyanawala, A. ; Pillai, Anilkumar R. / Repeated, intermittent exposures to diisopropylfluorophosphate in rats : Protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function. In: Neuroscience. 2011 ; Vol. 176. pp. 237-253.
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AU - Schwarz, G. M.

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