Chronic administration of diisopropyl fluorophosphate (DFP) at 72 hour intervals for a total of 14 doses resulted in a reduction in the number of central muscarinic receptors in mice as measured by the specific binding of [3H]Quinuclidinyl benzilate (QNB) to cortical tis sue homogenates (pmole/mg protein). The number of cholinergic receptors were reduced significantly by 12% in DFP treated animals (0.687 + 0.018 pmoles/mg) as compared to vehicle treated controls (0.781 +0.016 pmoles/ mg) after the sixth dose of DFP (Day 17). The decrease in the number of central cholinergic receptors was maximal after the 8th dose of DFP (Day 23), and central cholinergic receptor number remained significantly depressed through the 14th dose of DFP. DFP administration was termina ted after the 14th dose (Day 40), and the number of central cholinergic receptors increased to 0.853 + 0.013 pmole/mg after 6 days and returned to pretreatment levels (0.934 + 0.019 pmoles/mg) 13 days after the last dose of DFP. This study demonstrated that the number of central musca rinic receptors could be reduced by chronic DFP treatment, and binding could return to control levels after drug treatment was terminated. Hypoxia survival times were used to assess central cholinergic ac tivity. Therefore the next study was designed to examine the relation ship between DFP-induced alterations in central muscarinic receptor number and hypoxia survival times in mice during and following chronic administration with DFP at 72 hour intervals. At the first time point examined (Day 5, after the second dose of DFP) hypoxia survival times were significantly increased in DFP treated mice while receptor numbers were not significantly altered. Survival times of mice in hypoxic conditions were significantly increased after the 6th (Day 17), 12th (Day 35) and 14th doses (Day 41) of DFP, whereas the number of central cholinergic receptors was significantly reduced. The data from these three time points demonstrated that there is an inverse relationship between hypoxia survival times and the number of central muscarinic cholinergic receptors. Hypoxia survival times were not significantly altered 20 days (Day 60) after the last dose of DFP was administered, but the number of muscarinic receptors remained significantly depressed. On Days 5 and 60 the inverse relationship between hypoxia survival times and the number of central muscarinic receptors was not apparent. These studies demonstrate that the number of central cholinergic receptors can be altered during and following chronic DFP administra tion, but that hypoxia survival times were not a clear indicator of the number of central muscarinic receptors.
Library of Congress Subject Headings
Pharmaceutical chemistry; Chemistry, Analytic
Department, Program, or Center
School of Chemistry and Materials Science (COS)
Wallace, Kathleen B., "The Hypoxia Screen as an Indicator of Alterations in the Number of Centeral Cholinergic Recpetors Inuduced by Chronic Acetylcholinestrerase Inhibition" (1982). Thesis. Rochester Institute of Technology. Accessed from
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