Mechanism of Action of Phenytoin: Evidence for a Cerebellar Locus

  • D. W. McCandless
  • W. D. Lust
  • G. K. Feussner
  • J. V. Passonneau


The metabolic events in the brain associated with experimental seizures have been the subject of recent investigations in this laboratory. Maximal electroconvulsive shock (MES) has been used to induce seizures in mice (8, 9, 10). While the stimulus to the brain is undoubtedly excessive and does not exactly mimic the true seizure state, the nature and characteristics of the response are highly reproducible. Using this model, the effect of MES on cerebral and cerebellar energy metabolites and cyclic nucleotides has been investigated. The anticonvulsant, phenytoin, was demonstrated to have a locus of action in the whole cerebellum. Consequently, further studies were made on the effect of MES in the absence and presence of phenytoin on the layers of frozen-dried sections of the cerebellum in an attempt to localize more accurately the effects of convulsions and drug actions (4, 11).


Cerebral Cortex Purkinje Cell Cerebellar Cortex Cyclic Nucleotide Granular Layer 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Biggo, G., Brodie, B.B., Costa, E. and Guidotti, A. (1977): Mechanisms by which diazepam, muscimol, and other drugs change the content of cGMP in cerebellar cortex. Proc. Natl. Acad. Sci. USA, 74: 3592–3596.CrossRefGoogle Scholar
  2. 2.
    Bloom, F.E. (1975): The role of cyclic nucleotides in central synaptic function. Rev. Physiol. Biochem. Pharmacol. 74: 1–103.PubMedGoogle Scholar
  3. 3.
    Broddle, W. and Nelson, S.R. (1968): The effect of diphenylhydantoin on energy levels in brain. Fed. Proc. 27: 751.Google Scholar
  4. 4.
    Feussner, G.K., McCandless, D.W., Lust, W.D. and Passonneau, J.V. (1977): The effect of maximal electroshock on energy metabolites and cyclic nucleotides in layers of the cerebellar vermis. Society for Neuroscience. 3: 313.Google Scholar
  5. 5.
    Larsell, O. (1952): The morphogenesis and adult pattern of the lobules and fissures of the cerebellum of the white rat. J. Comp. Neurol. 97: 281–356.PubMedCrossRefGoogle Scholar
  6. 6.
    Lowry, O.H. and Passonneau, J.V. (1972): In: A Flexible System of Enzymatic Analysis. Academic Press, New York, 151–156.Google Scholar
  7. 7.
    Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall R.L. (1951): Protein measurement with the folin phenol reagent. J. Biol. Chem. 193: 265–275.PubMedGoogle Scholar
  8. 8.
    Lust, W.D., Goldberg, N.D. and Passonneau, J.V.(1976): Cyclic nucleotides in murine brain: The temporal relationship of changes induced in cyclic AMP and cyclic GMP following maximal electroshock or decapitation. J. Neurochem. 26: 5–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Lust, W.D., Kupferberg, H.J., Yonekawa, W.D., Penry, J.K. and Passonneau, J.V. Changes in brain metabolites induced by convulsants or electroshock: Effects of anticonvulsant agents. Molecular Pharmacology. (in press).Google Scholar
  10. 10.
    Lust, W.D. and Passonneau, J.V. (1976): Cyclic nucleotides in murine brain: Effect of hypothermia on cyclic AMP, glycogen Phosphorylase, glycogen synthase and metabolites following maximal electroshock or decpitation. J. Neurochem. 26: 11–16.Google Scholar
  11. 11.
    McCandless, D.W., Passonneau, J.V. and Lust, W.D. (1977): The effect of electroshock on energy metabolism in cerebellar layers. Anatomical Record. 187: 649.Google Scholar
  12. 12.
    Steiner, A.L., Wehmann, R.E., Parker, C.W. and Kipnis, D.M. (1972): Radioimmunoassay for the measurement of cyclic nucleotides. In: Advances in Cyclic Nucleotide Research. (Greengard, P. and Robinson, G.A., eds.). Raven Press, New York, 2: 51–61.Google Scholar
  13. 13.
    Stone, T.W., Taylor, D.A. and Bloom, F.E. (1975): Cyclic AMP and cyclic CMP may mediate opposite neuronal responses in the rat cerebral cortex. Science. 187: 845–847.PubMedCrossRefGoogle Scholar
  14. 14.
    Student (Gösset, W.S.) (1907): On the error of counting with a hemocytometer. Biometrika. 5: 351–360.Google Scholar

Copyright information

© Plenum Press, New York 1979

Authors and Affiliations

  • D. W. McCandless
    • 1
  • W. D. Lust
    • 1
  • G. K. Feussner
    • 1
  • J. V. Passonneau
    • 1
  1. 1.Laboratory of Neurochemistry, National Institute of Neurological and Communicative Disorders and StrokeNational Institutes of HealthBethesdaUSA

Personalised recommendations