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Noncholinesterase actions of an irreversible acetylcholinesterase inhibitor on synaptic transmission and membrane properties in autonomic ganglia

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Summary

  1. 1.

    Superfusion of the organophosphorous acetylcholinesterase inhibitor soman (pinacolyl methylphosphonofluoridate; 0.01–25µM) produced a dose-dependent reduction of extracellularly and intracellularly recorded synaptic responses in the isolated rat superior cervical ganglia at frequencies of orthodromic stimulation that do not normally produce synaptic depression. The magnitude of depression was dependent upon the frequency of stimulation (0.02–1 Hz), was maintained after the removal of soman from the superfusion solution, and recovered by over 65% during periods of inactivity.

  2. 2.

    The depression of synaptic transmission produced by soman was not dependent upon the inhibition of acetylcholinesterase (AChE) activity by this agent. Transmission was increasingly depressed by doses of soman greater than those needed to inactivate all measurable ganglionic AChE activity. Dose-dependent depression of synaptic transmission in soman also occurred after pretreatment with the irreversible AChE inhibitor diisopropylphosphofluoridate (DFP; 100µM), which inhibited greater than 98% of the AChE activity in the ganglia.

  3. 3.

    Soman produced a decline in the input resistance, resting potential, spike amplitude, and spike threshold and a reduction in the hyperpolarizing afterpotential.

  4. 4.

    Soman-induced depression of synaptic transmission was not due primarily to a blockade of postsynaptic nicotinic receptors. At concentrations of soman which produced significant depression in transmission, ganglionic depolarization produced by bath-applied carbamylcholine (carbachol) was either slightly depressed or facilitated.

  5. 5.

    In the presence of soman, repetitive focal application of acetylcholine or carbachol did not reveal use-dependent desensitization.

  6. 6.

    Muscarinic antagonists, atropine and pirenzepine, protected against the usedependent depression of synaptic transmission induced by soman. These results suggest that a principal site of action for soman is at the presynaptic terminal and that this site is sensitive to muscarinic receptor blockade.

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 21201, Baltimore, Maryland, USA

    Paul Yarowsky, John C. Fowler, Glen Taylor & Daniel Weinreich

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  1. Paul Yarowsky
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  2. John C. Fowler
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  3. Glen Taylor
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Yarowsky, P., Fowler, J.C., Taylor, G. et al. Noncholinesterase actions of an irreversible acetylcholinesterase inhibitor on synaptic transmission and membrane properties in autonomic ganglia. Cell Mol Neurobiol 4, 351–366 (1984). https://doi.org/10.1007/BF00733597

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  • DOI: https://doi.org/10.1007/BF00733597

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