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Research ArticleTOXICOLOGY

Delayed Neurologic and Behavioral Effects of Subtoxic Doses of Cholinesterase Inhibitors

Oscar U. Scremin, Tsung-Ming Shih, Ly Huynh, Margareth Roch, Ruth Booth and Donald J. Jenden
Journal of Pharmacology and Experimental Therapeutics March 2003, 304 (3) 1111-1119; DOI: https://doi.org/10.1124/jpet.102.044818
Oscar U. Scremin
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Tsung-Ming Shih
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Ly Huynh
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Margareth Roch
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Ruth Booth
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Donald J. Jenden
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Abstract

We tested the hypothesis that pyridostigmine bromide (PB) intake and/or low-level sarin exposure, suggested by some as causes of the symptoms experienced by Persian Gulf War veterans, induce neurobehavioral dysfunction that outlasts their effects on cholinesterase. Adult male Sprague-Dawley rats were treated during 3 weeks with s.c. saline, PB in drinking water (80 mg/l), sarin (62.5 μg/kg; 0.5× LD50, three times/week s.c.), or PB in drinking water + sarin. Animals were tested for passive avoidance, nociceptive threshold, acoustic startle, and open field activity 2, 4, or 16 weeks after treatment. Two weeks after sarin, acoustic startle was enhanced, whereas distance explored in the open field decreased. These effects were absent with PB + sarin or PB by itself. No effect on any variable was found at 4 weeks, whereas at 16 weeks sarin induced a decrease and PB + sarin induced an increase in habituation in the open field test. Nociceptive threshold was elevated in the PB + sarin group at 16 weeks. No effect of treatment on passive avoidance was noted in any group. Brain regional acetylcholinesterase and cholineacetyltransferase activities were not affected at any time after treatment, but muscarinic receptors were down-regulated in hippocampus, caudate putamen, and mesencephalon in the sarin group at 2 weeks. In conclusion, this study gives further support to the use of PB against nerve agent poisoning and does not support the hypothesis that delayed symptoms experienced by Persian Gulf War veterans could be due to PB, alone or in association with low-level sarin exposure.

Footnotes

  • This work was supported by a contract from the U.S. Army Medical Research and Material Command, DAMD 17-00 200015. Research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). The facilities where this research was conducted are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.

  • DOI: 10.1124/jpet.102.044818

  • Abbreviations:
    ChE
    cholinesterase
    PB
    pyridostigmine bromide
    OP
    organophosphorus
    BuChE
    butyrylcholinesterase
    ChAT
    cholineacetyltransferase
    AChE
    acetylcholinesterase
    RBC
    red blood cell
    QNB
    quinuclydinyl benzilate
    ANOVA
    analysis of variance
    LSD
    least significant difference
    F.U.
    force units
    • Received September 24, 2002.
    • Accepted November 19, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 3
1 Mar 2003
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Research ArticleTOXICOLOGY

Delayed Neurologic and Behavioral Effects of Subtoxic Doses of Cholinesterase Inhibitors

Oscar U. Scremin, Tsung-Ming Shih, Ly Huynh, Margareth Roch, Ruth Booth and Donald J. Jenden
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 1111-1119; DOI: https://doi.org/10.1124/jpet.102.044818

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Research ArticleTOXICOLOGY

Delayed Neurologic and Behavioral Effects of Subtoxic Doses of Cholinesterase Inhibitors

Oscar U. Scremin, Tsung-Ming Shih, Ly Huynh, Margareth Roch, Ruth Booth and Donald J. Jenden
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 1111-1119; DOI: https://doi.org/10.1124/jpet.102.044818
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