THE ANTICONVULSANT ACTION OF INHIBITORS OF CARBONIC ANHYDRASE: RELATION TO ENDOGENOUS AMINES IN BRAIN

¹ Department of Experimental Pharmacology, Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

Five hours after the administration of graded amounts of reserpine to mice, measurements were made of 1) the concentration of norepinephrine, 5-hydroxytraptamine and dopamine in brain, 2) excitability of brain and 3) the anticonvulsant potency of methazolamide, phenobarbital and diphenylhydantoin. The effect of methazolamide, a carbonic anhydrase inhibitor, was reduced and ultimately abolished ; phenobarbital and diphenylhydantoin were comparatively only slightly affected. To some degree, the reduction in the potency of these two agents, but not methazolamide, appeared to be related to the increase in the excitability of brain. Norepinephrine appears to be the amine normally required in brain in order for carbonic anhydrase inhibitors to have an anticonvulsant effect on the basis of the following. 1) Depletion of norepinephrine was the first significant concentration change to be associated with reduced anticonvulsant effect. 2) Dopamine does not appear involved because iproniazid prevented the antagonistic action of reserpine without effect on its depletion of this amine. Depletion of norepinephrine was prevented to a significant degree. 3) Repletion of norepinephrine, and possibly also dopamine, but not 5-hydroxytryptamine was associated with restoration of anticonvulsant effect. No explanation was found for the restorative action of methylphenidate.