EFFECTS OF CHRONIC ANTICONVULSANT ADMINISTRATION UPON CORTISONE-INDUCED BRAIN HYPEREXCITABILITY

¹ Department of Pharmacology, University of Edinburgh, Edinburgh, Scotland
² Department of Pharmacology, University of Utah College of Medicine, Salt Lake City, Utah

The effects of chronic administration of phenobarbital and diphenylhydantoin upon the normal electroshock seizure threshold and upon the cortisone-lowered threshold have been studied in rats. The repeated injection of phenobarbital did not elevate seizure threshold above that level obtainable by single doses. In sharp contrast, chronic administration of diphenylhydantoin significantly elevated seizure threshold whereas single doses are without effect. Possible reasons for these findings are presented. It is pointed out that laboratory evaluation of new antiepileptics should include potency determinations based on chronic administration in addition to the effects observed after acute single doses.

In confirmation of previous reports from this laboratory, the repeated injection of cortisone acetate has been found to cause a significant increase in brain excitability as measured by the threshold for minimal convulsions evoked by electroshock stimulation. After cortisone medication is withdrawn, approximately two weeks are required for the threshold to return to normal. Chronic administration of either phenobarbital or diphenylhydantoin is able to prevent the brain hyperexcitability induced by cortisone. When injections of the anticonvulsant are abruptly stopped, the electroshock seizure threshold rapidly falls to the level observed in animals receiving cortisone alone. When a single appropriate dose of phenobarbital or diphenylhydantoin is given to animals with cortisone-induced brain hyperexcitability, the lowered seizure threshold is promptly elevated to normal. Reasons are presented for tentatively concluding that cortisone increases excitability by a direct action on the brain and not via a change in body weight or nutritional status. It is also concluded that the mechanism by which anticonvulsants elevate seizure threshold is different from that by which cortisone induces brain hyperexcitability, and that phenobarbital and diphenylhydantoin merely mask the effects of cortisone on brain function. The clinical implications of the experimental results are briefly discussed, and the potential value of anticonvulsants for the prevention as well as the treatment of convulsive seizures in patients receiving cortisone or ACTH is noted. The suggestion is made that animals with cortisone-reduced electroshock seizure thresholds may provide a useful means for the assay of anticonvulsant drugs.

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				J. E. HARRIS PHARMACOLOGY AND TOXICOLOGY Arch Ophthalmol, August 1, 1953; 50(2): 192 - 247. [PDF]