THE MECHANISM OF THE ANTAGONISTIC ACTION OF RESERPINE ON THE ANTICONVULSANT EFFECT OF INHIBITORS OF CARBONIC ANHYDRASE

¹ Department of Experimental Pharmacology, Experimental Therapeutics Research Section, Lederle Laboratories Division, American Cyanamid Co., Pearl River, New York

Antagonism of the anticonvulsant action of inhibitors of carbonic anhydrase in mice by reserpine was shown not to be due to any effect of this agent on brain with respect to 1) the concentration of inhibitor, 2) the activity of carbonic anhydrase, 3) the intracellular localization of enzyme and inhibitor, or 4) the interaction of enzyme and inhibitor. Competition between agents with opposing actions on the excitability of brain was also excluded as a mode of action. Because methyldopa and tetrabenazine were also able to antagonize the action of methazolamide, depletion of brain amines appeared to be the causative factor. Since the anticonvulsant action of methazolamide could be restored by pretreatment with monoamine oxidase inhibitors or by the administration of dihydroxyphenylalanine (dopa), but not by nearly equivalent amounts of tryptophan or 5-hydroxytryptophan, it was concluded that the presence of catecholamines in brain is necessary in order for inhibitors of carbonic anhydrase to exhibit their anticonvulsant effect.