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Research Topics
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Genetic Studies
Project Summary

Title: Effects of Genetics and Stress on Responses to Environmental Toxins
Synopsis: The project sought to determine whether genetic susceptibility to stress and exposure to chronic stress resulted in heightened sensitivity to the effects of pyridostigmine bromide (PB), and hydrocarbons from oil well fires.
Overall Project Objective: This project will determine whether genetic susceptibility to stress and exposure to chronic stress will result in persistent sensitization to potentially toxic effects of pyridostigmine bromide and aromatic hydrocarbons. In addition, it will examine the behavioral consequences of chronic exposure to these toxins.
Status/Results to Date: We have been unable to validate the behavioral hyper-responsiveness in WKY rats that has been reported by others. Preliminary data suggest that pyridostigmine bromide may cause a substantial decrease in voluntary running activity in rats, but it is unclear as yet whether this could be a long-term effect. However, it is clear that WKY rats are more sensitive to some effects of pyridostigmine bromide than SD rats. For example, WKY rats show an exaggerated startle response 1 to 3 weeks after ending pyridostigmine bromide treatment that is not present earlier and does not develop in SD rats. These results have led to the current studies of interactions among strain, chronic stress, and potential pyridostigmine bromide toxicity. This project was terminated in December 1997. Continuation of this project has been funded under a VA Merit Review grant to Dr. Richard Servatius. See Project # VA-49.
Project:VA-5D
Agency:Department Of Veterans' Affairs
Location:VAMC East Orange
P.I. Name:J E Ottenweller, Ph. D.
Research Type:Mechanistic
Research Focus:Pyridostigmine Bromide
Focus Category:Genetic Studies
Status:Complete
Study Start Date:October 01,1994
Estimated Completion Date:September 30,1997
Specific Aims: 1) To expose Wistar-Kyoto (WKY) rats (stress-hyper responsive) and Sprague-Dawley (SD) rats (control) rats to chronic stress and then study the sensitivity to pyridostigmine bromide by measuring startle and neuroendocrine responses; and the sensitivity to aromatic hydrocarbons by measuring the activity of hepatic enzymes induced to metabolize these compounds. 2) To treat WKY and SD rats chronically with these compounds and examine behavioral rhythms, temperature rhythms, startle responsiveness, and neuroendocrine function (both basally and in response to stress).
Methodology: SD and WKY rats will be treated with pyridostigmine bromide for 7 days and for the last 3 days will be subjected to a chronic stress regime. 24 hours after the last stressor exposure, the neuroendocrine and brain c-fos responses to pyridostigmine bromide will be evaluated, as well as the levels of specific isozymes of cytochrome P-450 in the liver. These enzymes are responsible for the metabolism of a large group of xenobiotics, including aromatic hydrocarbons. The changes in these enzyme levels will also be evaluated following stressor exposures and subsequent exposure to aromatic hydrocarbons. Similar studies will determine the behavioral and some physiological effects of chronic treatment with pyridostigmine bromide and aromatic hydrocarbons, as well as their effects on the responses to chronic stress.
Most Recent Publications:

Beck K, Zhu G, Beldowicz D, Brennan FX, Ottenweller JE, Moldow RL, Servatius R. Central nervous system effects from a peripherally acting cholinesterase inhibiting agent: Interaction with stress or genetics. Ann N Y Acad Sci, 933:310-314, No abstract available. Mar 2001. Reviews

Servatius R, Ottenweller JE, Guo WD, Beldowicz D, Zhu G, Natelson BH. Effects of inescapable stress and treatment with pyridostigmine bromide on plasma butyrylcholinesterase and the acoustic startle response of rats. Physiology and Behavior, 69(3):239-46, May 2000. Abstract

Ottenweller JE, Servatius R, Zhu G, Beldowicz D, Natelson BH. Persistent changes in physiology and behavior after pyridostigmine in rats with low BuCHE. Conference on Federally Sponsored Gulf War Veterans Illnesses Research, Washington, DC, 1998. Conference

Servatius R, Ottenweller JE, Beldowicz D, Guo WD, Zhu G, Natelson BH. Persistently exaggerated startle responses in rats treated with pyridostigmine bromide. Journal of Pharmacology and Experimental Therapeutics, 287(3):1020-1028, Dec 1998. Abstract

Beck K, Brennan FX, Moldow RL, Ottenweller JE, Zhu G, Servatius RJ. Stress interacts with peripheral cholinesterase inhibitors to cause central nervous system effects. Life Sci, 73(1):41-51. May 2003. Abstract