Dependence of anticonvulsant drug action on central monoamines

Abstract

In mice, the influence of receptor blocking drugs and variations in the central levels and metabolism of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT) on the effect of certain anticonvulsant drugs was studied. The effect of phenobarbital against electro-convulsions was antagonized by treatments lowering central 5-HT or noradrenaline, as well as by cyproheptadine and phentolamine. 5-Hydroxytryptophan (5-HTP) and l-DOPA had a synergistic effect. These results point to an important participation of 5-HT and noradrenaline in the anticonvulsant effect of phenobarbital. The anticonvulsant activity of diphenylhydantoin in the maximal electroshock seizure test decreased after treatmentwithα-methyltyrosine and disulfiram, and noradrenaline seems thus to play a role for the effect of the drug. A participation of 5-HT remains doubtful since only p-chlorophenylalanine had a weak antagonistic action but cyproheptadine and 5-HTP were without influence on the ED 50. In the pentetrazole seizure threshold test, phenobarbital was antagonized by p-chlorophenylalanine and cyproheptadine whereas 5-HTP had a synergistic effect. A participation of 5-HT in the mediation of the anticonvulsant action of the drug therefore seems obvious, but indications for a role also of noradrenaline were less convincing. Results with ethosuximide were similar regarding the role of 5-HT, but experiments on the role of catecholamines gave conflicting results. A comparison of the present results with those of a previous study on the importance of the central monoamines for convulsive thresholds shows that changes in anticonvulsant ED 50 values induced by interferences with the central monoamines do not merely follow the simultaneous changes in convulsive threshold.