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Pharmacology of the Inhibitory Systems in Primary Generalized Epilepsy of “Petit Mal” Type

  • R. G. Fariello

Abstract

That the neurochemical substrate of bilaterally synchronous spikes-and-wave (SW) discharges differs substantially from the one of focal epilepsy appeared evident to us about 10 years ago while we were studying the effect of homotaurine (3-aminopropanesulfonic acid, 3APS), a highly specific GABA agonist, on various seizure models, in view of its potential use as an antiepileptic agent. An intravenous injection of 3APS in cats with an acute neocor-tical focus induced by topical application of penicillin provoked a transient suppression of all focal epileptiform discharges associated with systemic phenomena such as bradycardia, hypertension, and dyspnea (Fariello, 1979). When a pattern of bilaterally synchronous SW discharges was induced by systemic penicillin injection, however intravenous 3APS at the dose capable of suppressing focal spikes induced a remarkable potentiation of the SW complexes, which lasted several minutes and was accompanied by the same systemic effects (Fariello et al., 1981). In view of the fact that in the same animal species two epileptiform phenomena induced by the same epileptogenic agent showed diametrically opposite responses to the same Gaba agonist administered at the same dose through the same route and causing the same systemic phenomena, it appeared reasonable to ascribe the discrepancy of the two responses to a different role played by GABA-mediated inhibition in the two seizure models. Review of the available literature confirmed that several other models of bilaterally synchronous SW discharges were enhanced by the administration of direct or indirect GABA agonists. The bilaterally synchronous SW discharge elicited by photic stimulation in the baboon Papio papio is potentiated by administration of muscimol, a powerful direct GABAA agonist (Pedley et al., 1979). Other partial or indirect agonists, such as gammahydroxybutyrate and imidazole-4-acetic acid, potentiate models of SW epileptiform activity (Marcus et al., 1971; King, 1979; Snead, 1978). Also, in rats, agents that block GABA transaminase, which presumably increases GABA availability in the synaptic cleft, markedly potentiate metrazol-induced SW discharges (Myslobodsky et al., 1979). In the following years, several studies further confirmed this seizure-enhancing effect of GABA agonists on bilaterally synchronous SW. In rodents, the gamma hydroxybutirate-induced model of petit mal is remarkably facilitated by the administration of several GABA-mimetics (Snead, 1984). Furthermore, administration of such direct GABA agonists as 4,5,6,7 tetrahydroxyisoxasolo (4,5-c) pyridine 3-ol (THIP) and muscimol induced in several animal species de novo epileptiform abnormalities. In particular, in rats, three stages of EEG epileptiform phenomena are seen after incremental doses of these two direct GABAA agonists: Isolated spikes are first seen, then bilaterally synchronous SW discharges, and eventually, with the higher doses, a burst-suppression pattern appears (Golden and Fariello, 1984). Actually the administration of THIP to Sprague-Dawley albino or Long Ev-ans hooded rats at doses between 5 to 10 mg/kg induces a sustained pattern of 5- to 7-Hz SW discharges that are remarkably similar to the one observed spontaneously in several rodent species (Fariello and Golden, 1987). This spontaneous high voltage spindle-like (HSV) activity is now being accepted as a model of petit mal epilepsy, in spite of a continuing controversy about whether it is epileptic or nonepileptic in nature (Kaplan, 1985). In recent studies, HSVs were enhanced by direct GABA agonists, by GABA transaminase antagonists, and GABA uptake inhibitors (Marescaux et al., in press).

Keywords

Focal Epilepsy Seizure Model Gaba Agonist Cortical Excitation Primary Generalize Epilepsy 
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.

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References

  1. Buchwald, N.A., Hull, C.D., and Trachtenberg, M., 1967, Concomitant behavior and neural inhibition and disinhibition in response to subcortical stimulation, Exp. Brain Res. 4: 58.CrossRefGoogle Scholar
  2. Buzsaki, G., Bickford, R.G., Ponomareff, G., Thal, L.J., Mandel, R., and Gage, F.H., 1988, Nucleus basalis and thalamic control of neocortical activity in the freely moving rat, J. Neuros ci. 8: 4007.Google Scholar
  3. Ente, P., Golden, G.T., and Fariello, R.G., 1986, Neuropharmacological analysis of caudate-induced cortical inhibition, Functional Neurol. 1: 269.Google Scholar
  4. Fariello, R., 1979, Forebrain influences on an acute amygdaloid focus in the cat, Exp. Neurol. 66: 55.CrossRefGoogle Scholar
  5. Fariello, R.G., 1984, The role of GABAergic mechanisms in the epilepsies, in: Advances in Epilep-tology: XVth Epilepsy International Symposium (R.J. Porter, R.H. Mattson, A.A. Ward, Jr., and M. Dam, eds.), Raven Press, New York, pp. 17–24.Google Scholar
  6. Fariello, R.G., and Golden, G.T., 1987, The THIP-induced model of bilateral synchronous spike and wave in rodents, Neuropharmacology 26: 161.CrossRefGoogle Scholar
  7. Fariello, R.G., Golden, G.T., and Black, J.A., 1981, Activating effects of homotaurine and taurine on corticoreticular epilepsy, Epilepsia 22: 217.CrossRefGoogle Scholar
  8. Gale, K., 1984, Role of the substantia nigra in the anticonvulsant action of GABAergic drugs, in: Neurotransmitter, Seizures and Epilepsy II (R.G. Fariello, P.L. Morselli, K.G. Lloyd, L.F. Quesney, and J. Engel, Jr., eds.), Raven Press, New York, pp. 37–47.Google Scholar
  9. Gloor, P., and Fariello, R.G., 1988, Generalized epilepsy: Some of its cellular mechanisms differ from those of focal epilepsy, Trends Neurosci. 11: 63.CrossRefGoogle Scholar
  10. Gloor, P., Pellegrini, A., and Kostopoulos, G.K., 1979, Effects of changes in cortical excitability upon the epileptic bursts in generalized penicillin epilepsy of the cat, Electroencephalogr. Clin. Neurophysiol. 46: 274.CrossRefGoogle Scholar
  11. Golden, G.T., and Fariello, R.G., 1984, Epileptogenic action of some direct GABA agonists: Effects of manipulation of the GABA and glutamate systems, in: Neurotransmitters, Seizures and Epilepsy II (R.G. Fariello, P.L. Morselli, K.G. Lloyd, L.F. Quesney and J. Engel, Jr., eds.), Raven Press, New York, pp. 37–47.Google Scholar
  12. Kaplan, B., 1985, The epileptic nature of rodent electrocortical polyspiking is still unproven, Exp. Neurol. 88: 425.CrossRefGoogle Scholar
  13. King, G.A., 1979, Effects of systemically applied GABA agonists and antagonists on wave-spike EEG activity in rat, Neuropharmcology 13: 47.CrossRefGoogle Scholar
  14. Marcus, R.J., Winters, W.D., Roberts, E., and Simonsen, D.G., 1971, Neuropharmacological studies of imidazole-4-acetic acid actions in the mouse and the rat, Neuropharmacology 10: 203.CrossRefGoogle Scholar
  15. Marescaux, C., Vergnes, M., Depaulis, A., Micheletti, G., and Waiter, J.M., 1989, Neurotransmission in rats, spontaneous generalized noncon-vulsive epilepsy, in: Neurotransmitters, Seizures and Epilepsy (G. Avanzini, R.G. Fariello, J. Engel, Jr., and U. Heinemann, eds.), Demos Publications, New York, in press.Google Scholar
  16. Myslobodsky, M.S., Ackermann, R.F., and Engel, J., Jr., 1979, Effects of gamma acetylenic GABA and gamma-vinyl-GABVA on metrazol-activated and-kindled seizures, Pharmacol. Biochem. Behav. 11: 265.CrossRefGoogle Scholar
  17. Pedley, T.A., Horton, R.W., and Meldrum, B.S., 1979, Electronencephalographic and behavioral effects of a GABA agonist (Muscimol) on photosensitive epilepsy in the baboon Papio papio, Epilepsia 20: 409.CrossRefGoogle Scholar
  18. Snead, O.C., 1978, Gamma hydroxybutyrate in the monkey. I. Electroencephalographic behavioral and pharmacokinetic studies. Neurology 28: 636.Google Scholar
  19. Snead, O.C., III, 1984, Gamma-hydroxybutyric acid, gamma aminobutyric acid and petit mal epilepsy, in: Nerurotransmitter, Seizures and Epilepsy II (R.G. Fariello, P.L. Morselli, K.G. Lloyd, L.F. Quesney, and J. Engel, Jr., eds.), Raven Press, New York, pp. 37–47.Google Scholar
  20. Tremblay, N., Warren, R., and Dykes, R.W., 1988, The effects of strychnine on neurons in cat somatosensory cortex and its interaction with the inhibitory amino acids, glycine taurine and βalanine, Neuroscience 26: 745.CrossRefGoogle Scholar

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© Birkhäuser Boston, Inc. 1990

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  • R. G. Fariello

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