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ToxSci Advance Access published online on March 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi151
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received January 24, 2005
Accepted March 4, 2005

Systems Toxicology

Miotic tolerance to sarin vapor exposure: role of the sympathetic and parasympathetic nervous systems

Paul A. Dabisch 1*, Dennis B. Miller 2, Sharon A. Reutter 3, Robert J. Mioduszewski 3, and Sandra A. Thomson 3

1 National Research Council Postdoctoral Associate, National Academy of Sciences, Washington, D.C., USA; U.S. Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD, USA
2 Geo-Centers, Inc., Gunpowder, MD, USA
3 U.S. Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD, USA

* To whom correspondence should be addressed.
Paul A. Dabisch, E-mail: paul.dabisch{at}us.army.mil


  Abstract

O-isopropyl methylphosphonofluoridate, also known as sarin or GB, is a highly toxic organophosphorous compound that exerts its effect by inhibiting the enzyme acetylcholinesterase. While the effects of a single exposure to GB vapor are well characterized, the effects of multiple exposures to GB vapor are less clear. Previous studies in the rat and guinea pig have demonstrated that multiple exposures result in tolerance to the miotic effect of nerve agents. The aim of the present study was to examine potential mechanisms responsible for the tolerance to the miotic effect of GB vapor observed in the rat following multiple exposures. Multiple whole-body inhalation exposures to GB vapor were conducted in a dynamic airflow chamber. Exposures lasted 60 minutes and each of the 3 exposures occurred at 24-hour intervals. The results of the present study demonstrate that the {alpha}-adrenergic antagonist, phentolamine, and the {beta}-adrenergic receptor antagonist, propranolol, did not affect the development of tolerance to the miotic effect of GB vapor, suggesting that enhanced sympathetic tone to the eye is not responsible for the observed tolerance. Administration of atropine before the first exposure prevented the tolerance to the miotic effect of GB vapor following the third exposure, suggesting that the tolerance is the result of muscarinic receptor desensitization secondary to receptor stimulation. The present study extends the findings of previous studies to strengthen the hypothesis that the miotic tolerance observed in the rat upon repeated exposure to nerve agents is due to desensitization of muscarinic acetylcholine receptors located on the pupillary sphincter.


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P. A. Dabisch, F. To, E. K. Kerut, M. S. Horsmon, and R. J. Mioduszewski
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