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Research Topics
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Genetic Studies
Project Summary

Title: Effects of Pyridostigmine in Flinders Line Rats Differing in Cholinergic Sensitivity
Synopsis: An animal (rat) model study to predict and compare effects of pyridostigmine bromide (PB) administered for a short time and continually.
Overall Project Objective: Test the hypothesis that a genetically based cholinergic supersensitivity might underlie the increased sensitivity of vulnerable human populations, similar to the condition labeled Multiple Chemical Sensitivity (MCS).
Status/Results to Date: The investigators confirmed that the FSI, rats exhibit greater increases in serum growth hormone following acutely administered pyridostigmine. The investigators suggested that, in this regard, the animals resemble depressed individuals, who exhibit a greater growth hormone response to pyridostigmine compared to normal controls. The greater sensitivity to pyridostigmine did not translate to altered protection against other anticholinesterases following chronic treatment with pyridostigmine. Rats that were chronically treated with pyridostigmine appeared to exhibit greater short-term decreases in temperature following the acute administration of diisopropyl fluorophosphate or chlorpyrifos. Thus, chronic treatment with pyridostigmine made the rats more sensitive to the subsequent injection of the anticholinesterases in the periphery, while the other agents inhibit cholinesterases in the brain as well as the periphery. Work during the final year of study suggests that pyridostigmine is not an effective prophylactic against central effects of ogranophosphates but that physotigmine is effective in countering hypothermia induced by organophosphates.
Project:DoD-33
Agency:Department Of Defense
Location:University of North Carolina, Chapel Hill
P.I. Name:David H Overstreet, Ph. D.
Research Type:Mechanistic
Research Focus:Pyridostigmine Bromide
Focus Category:Genetic Studies
Status:Complete
Study Start Date:July 01,1996
Estimated Completion Date:June 30,1999
Specific Aims: Determine strain-dependent effects of acute and chronically administered pyridostigmine. Determine whether chronic pyridostigmine will protect against effects of other anticholinesterase agents. This will be accomplished by developing an animal model with cholinergic supersensitivity which is also more sensitive to a variety of drugs and other chemical agents.
Methodology: Rats will be treated with pyridostigmine acutely or chronically and growth hormone, body temperature, and locomotor activity will be assessed. The Flinders Line rats developed at Flinders University in Australia by selective breeding for differential responses to the anticholinesterase, diisopropyl fluorophosphate (DFP). These rats have been shown to be more sensitive to directly acting muscarinic agonist, as well as a variety of other drugs including alcohol, diazepam, and nicotine. The heightened sensitivity of this special line of rats to a variety of drugs suggests that they will also be more sensitive to the effects of pyridostigmine, an anticholinesterase drug which was given to soldiers during ODS.
Most Recent Publications:

Overstreet DH, Rezvani AH, Yang Y, Hamedi M, Janowsky DS. Animal model of chemical sensitivity involving cholinergic agents. Toxicology in Risk Assessment Symposium, Chapter Nine, PP75-94, 2001. Article

Overstreet DH, Daws LC, Schiller GD, Janowsky DS, Orbach J. Cholinergic/serotonergic interactions in hypothermia: implications for rat models of depression. Pharmacol Biochem Behav, 59(4):777-85, Apr 1998. Abstract

Overstreet DH, Yang Y, Rezvani AH. Failure of Pyridostigmine Pretreatment to Protect against the Effects of Chlorpyrifos. Conference on Federally Sponsored Gulf War Veterans Illnesses Research, June 17-19, 1998. Abstract

Overstreet DH, Yang Y, Clark E, Rezvani AH. More rapid decreases in temperature following anticholinesterase challenges in rats pretreated with pyridostigmine. 16th International Neurotoxicology Conference, Little Rock, Arkansas, September 13-16, 1998. Abstract

Overstreet DH, Yang Y, Hamedi M, Janowsky DS, Rezvani AH. Strain-and Gender-dependent effects of oxotremorine and pyridostigmine. Society for Neuroscience, New Orleans, LA, 1997. Abstract

Overstreet DH, Mason GA, Yang Y, Rezvani AH. Supersensitive growth hormone responses following pyridostigmine challenge in a genetic animal model of depression. 28th Annual Meeting of the Society for Neuroscience, 189, 10, Meeting Held In Los Angeles, CA, Nov 7-12, 1998. Abstract