Organophosphorus Anticholinesterase-Induced Epileptiform Activity in the Hippocampus

  • Frank J. Lebeda
  • Paul A. Rutecki


In the study of epileptogenesis, the pharmacological induction of convulsant activity has provided important information regarding the cellular events involved in the production of abnormal electrical discharges. This research approach has benefited from the advent of in vitro central nervous system (CNS) tissue slices and the use of microelectrode recording techniques (Yamamoto, 1972). Synchronous repetitive discharges induced by the drugs examined thus far are the characteristic features of the epileptiform activity recorded in vivo and in vitro. These discharges are considered to be correlated with abnormal interictal electroencephalographic (EEG) recordings (Ayala et al., 1973). The corresponding intracellular event is comprised of a series of action potentials superimposed on an envelope of depolarization. This envelope of depolarization was termed the paroxysmal depolarizing shift (PDS) by Matsumoto and Ajmone Marson (196M) in characterizing penicillin-induced discharges in vivo. Recent studies have shown that the event underlying the drug-induced PDS is a net excitatory response produced by a synchronous synaptic input (Johnston and Brown, 1981; Lebeda et al., 1982).


Reversal Potential Epileptiform Activity Discharge Frequency Extracellular Recording Inhibitory Synaptic Transmission 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aldridge, W. N., 1953, The inhibition of erythrocyte cholinesterase by tri-esters of phosphoric acid. 3. The nature of the inhibitory process, Biochem. J, 54: 442–448.PubMedGoogle Scholar
  2. Andersen, P., and Langmoen, I. A., 1980, Intracellular studies on transmitter effects on neurones in isolated brain slices, Q. Rev. Biophys, 13: 1–18.PubMedCrossRefGoogle Scholar
  3. Ayala, G. F., Dichter, M., Gumnit, R. J., Matsumoto, H., and Spencer, W. A., 1973, Genesis of epileptic interictal spikes. New knowledge of cortical feedback systems suggests a neurophysiological explanation of brief paroxysms, Brain Res, 52: 1–17.PubMedCrossRefGoogle Scholar
  4. Bernardo, L. S., and Prince, D. A., 1981, Acetylcholine induced modulation of hippocampal pyramidal neurons, Brain Res, 211: 227–234.CrossRefGoogle Scholar
  5. Brimblecombe, R. W., 1974, “Drug Actions on Cholinergic Systems,” University Park Press, Baltimore.Google Scholar
  6. Brown, D. A., and Adams, P. R., 1980, Muscarinic suppression of a novel voltage-sensitive K current in a vertebrate neurone, Nature, 283: 673–676.PubMedCrossRefGoogle Scholar
  7. Brown, T. H., and Johnston, D., 1983, Voltage-clamp analysis of mossy fiber synaptic input to hippocampal neurons, J. Neurophysiol, 50: 487–507.PubMedGoogle Scholar
  8. Cole, A. E., and Nicoll, R. A., 1983, Acetylcholine mediates a slow synaptic potential in hippocampal pyramidal cells, Science, 221: 1299–1301.PubMedCrossRefGoogle Scholar
  9. Dingledine, R., and Gjerstad, L., 1980, Reduced inhibition during epileptiform activity in the in vitro hippocampal slice, J. Physiol. (Lond.), 305: 297–313.Google Scholar
  10. Ellin, R. I., 1982, Anomalies in theories and therapy of intoxication by potent organophosphorus anticholinesterase compounds, Gen. Pharmacol, 13: 457–466.PubMedCrossRefGoogle Scholar
  11. Ellman, G. L., Courtney, K. D., Andres, V., and Featherstone, R. M., 1961, A new and rapid colorimetric determination of acetylcholinesterase activity, Biochem. Pharmacol, 7: 88–95.PubMedCrossRefGoogle Scholar
  12. Haas, H. L., Schaerer, B., and Vosmansky, M., 1979, A simple perfusion chamber for the study of nervous tissue slices in vitro, J. Neurosci. Meth, 1: 323–325.CrossRefGoogle Scholar
  13. Halliwell, J. V., and Adams, P. R., 1982, Voltage-clamp analysis of muscarinic excitation in hippocampal neurons, Brain Res, 250: 71–92.PubMedCrossRefGoogle Scholar
  14. Hampson, J. L., Essig, C. F., McCauley, A., and Himwich, H. E., 1950, Effects of di-isopropyl fluorophosphate (DFP) on electroencephalogram and cholinesterase activity, Electroencephalogr. Clin. Neurophysiol, 2: 41–48.CrossRefGoogle Scholar
  15. Harwood, C. T., 1954, Cholinesterase activity and electroencephalograms during circling induced by the intracarotid injection of di-isopropyl fluorophosphate (DFP), Amer. J. Physiol, 177: 171–174.PubMedGoogle Scholar
  16. Johnston, D., 1981, Passive cable properties of hippocampal CA3 neurons, Cell. Mol. Neurobiol, 1: 45–55.CrossRefGoogle Scholar
  17. Johnston, D., and Brown, T. H., 1981, Giant synaptic potential hypothesis for epileptiform activity, Science, 211: 294–297.PubMedCrossRefGoogle Scholar
  18. Johnston, D., and Brown, T. H., 1984, Biophysics and microphysiology of synaptic transmission in hippocampus, in: “Brain Slices,” R. Dingledine, ed., Plenum, New York.Google Scholar
  19. Johnston, D., Hablitz, J. J., and Wilson, W. A., 1980, Voltage clamp discloses slow inward current in hippocampal burst-firing neurones, Nature, 286: 391–393.PubMedCrossRefGoogle Scholar
  20. Johnston, D., Rutecki, P. A., and Lebeda, F. J., Synaptic events underlying spontaneous and evoked paroxysmal discharges in hippocampal neurons, Plenum, New York, (in press).Google Scholar
  21. Karczmar, A. G., 1967, Pharmacologic, toxicologic, and therapeutic properties of anticholinesterase agents, In: “Physiological Pharmacology,” W. C. Root, and F. G. Hoffman, eds., Part C, Vol. 3, Academic Press, New York.Google Scholar
  22. Krnjevic, K., Pumain, R., and Renaud, L., 1971, The mechanism of excitation by acetylcholine in the cerebral cortex, J. Physiol. (Lond.), 215: 247–268.Google Scholar
  23. Krnjevic, K., Randic, M., and Straughan, D. W., 1966, Pharmacology of cortical inhibition, J. Physiol. (Lond.), 184: 78–105.Google Scholar
  24. Kuba, K., Albuquerque, E. X., Daly, J., and Barnard, E. A., 1974, A study of the irreversible cholinesterase inhibitor, diisopropylfluorophosphate, on time course of endplate currents in frog sartorius muscle, J. Pharmacol. Exp. Ther, 189: 499–512.PubMedGoogle Scholar
  25. Lebeda, F. J., Hablitz, J. J., and Johnston, D., 1982, Antagonism of GABA-induced responses by d-tubocurarine in hippocampal neurons, J. Neurophysiol, 48: 622–632.PubMedGoogle Scholar
  26. Lebeda, F. J., Rutecki, P. A., and Johnston, D., 1983, Synaptic mechanisms action of convulsion-producing anticholinesterases, Def. Tech. Info. Center, DA-300017, Alexandria, Virginia.Google Scholar
  27. Lebeda, F. J., and Rutecki, P. A, 1985, Characterization of spontaneous epileptiform discharges induced by organophosphorus anticholinesterases in the in vitro rat hippocampus, Proc. West. Pharmacol. Soc, 28: 187–190.PubMedGoogle Scholar
  28. Lipp, J. A., 1972, Effect of diazepam upon soman-induced seizure activity and convulsions, Electroencephalogr. Clin. Neurqphysiol, 32: 557–560.Google Scholar
  29. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J., 1951, Protein measurement with Folin phenol reagent, J. Biol. Chem, 193: 265–275.PubMedGoogle Scholar
  30. Machne, X., and Unna, K. R. W., 1963, Actions at the central nervous system, in: “Cholinesterases and Anticholinesterases,” G.B. Koelle, ed., ( Handbuch der Experimentellen Pharmakologie, Vol. 15 ), Springer-Verlag, Berlin.Google Scholar
  31. Main, A. R., 1964, Affinity and phosphorylation constants for the inhibition of esterases by organophosphates, Science, 144: 992–993.PubMedCrossRefGoogle Scholar
  32. Matsumoto, H., and Ajmone Marsan, C., 1964, Cortical cellular phenomena in experimental epilepsy: interictal manifestations, Exp. Neurol, 9: 286–304.PubMedCrossRefGoogle Scholar
  33. O’Neill, J. J., 1981, Non-cholinesterase effects of anticholinesterases, Fundam. Appl. Pharmacol, 1: 154–160.CrossRefGoogle Scholar
  34. Rump, S., Grudzinska, E., and Edelwejn, Z., 1973, Effects of diazepam on epileptiform patterns of bioelectrical activity of the rabbit’s brain induced by fluostigmine, Neuropharmacology, 12: 813–817.PubMedCrossRefGoogle Scholar
  35. Rutecki, P. A., Lebeda, F. J., and Johnston, D., 1984, Elevated extra-cellular potassium- and 4-aminopyridine-induced epileptiform activity in CA3 hippocampal neurons, Soc. Neurosci. Abstr, 10: 1.Google Scholar
  36. Rutecki, P. A., Lebeda, F. J., and Johnston, D., Epileptiform activity induced by changes in extracellular potassium in the hippocampus, J. Neurophysiol. (in press).Google Scholar
  37. Schwartzkroin, P. A., and Prince, D. A., 1980, Changes in excitatory and inhibitory synaptic potentials leading to epileptogenic activity, Brain Res, 183: 61–73.PubMedCrossRefGoogle Scholar
  38. Valentino, R. J., and Dingledine, R., 1981, Presynaptic inhibitory effect of acetylcholine in the hippocampus, J. Neurosci, 1: 784–792.PubMedGoogle Scholar
  39. Van Meter, W. G., Karczmar, A. G., and Fiscus, R. R., 1978, CNS effects of anti-cholinesterases in the presence of inhibited cholinesterases, Arch. Int. Pharmacodyn, 231: 249–260.PubMedGoogle Scholar
  40. Yamamoto, C.7 1972, Intracellular study of seizure-like afterdischarges elicited in thin hippocampal sections in vitro, Exp. Neurol, 35: 154–164.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Frank J. Lebeda
    • 1
  • Paul A. Rutecki
    • 1
  1. 1.Section of Neurophysiology, Department of Neurology Epilepsy Research CenterBaylor College of MedicineHoustonUSA

Personalised recommendations