Interaction of Convulsant and Anticonvulsant Drugs with Endogenous Amines

Abstract

Evidence of an interaction of adrenergic pathways with convulsive mechanisms was sufficient to warrant an experimental study of leptazol-induced convulsions. Spectrophotofluorometric assays of noradrenaline (and adrenaline), dopamine, and 5-HT, based on the methods of Bertler, Carlsson, and Rosengren (1958), Carlsson and Lindqvist (1962), and Cox and Potkonjak (1967) respectively, were developed. Catecholamine and 5-hydroxytryptamine concentrations were determined in whole brain and discrete areas of rat brain before, during, and after leptazol convulsions. No significant effect was detected under these conditions. Elevation of amine concentrations with five representative MAO inhibitors (tranyleypromine, phenelzine, iproniazid, pargyline, and nialamide) was without effect on leptazol threshold. Tranylcypromine, phenelzine, and iproniazid possessed a transient proconvulsant action similar to that of dexamphetamine, which correlated with their inherent sympathomimetic activity. COMT inhibitors (pyrogallol, catechol, and p-thujaplicin) were without effect on leptazol threshold. Specific blockade of any one amine synthesis with either o-methyl-p-tyrosine, diethyldithiocarbamate, or p-chlorophenylalanine, or blockade of all three syntheses simultaneously, was also without effect on leptazol threshold. Reserpine, syrosingopine, or A-methyl-m-tyrosine were proconvulsant but only in doses and combinations that depleted all three amines simultaneously by at least 80-85%. Selective repletion of any one amine store to 50% of the control concentrations totally abolished this proconvulsant activity. It is concluded that the disposition of the amine stores, rather than the state of the syntheses, is involved in any proconvulsant activity.

The anticonvulsants phenobarbitone, phenytoin, and chlordiazepoxide were examined under similar conditions. Blockade of catecholamine synthesis reduced the anticonvulsant activity of chlordiazepoxide; so too did depletion of catecholamine stores with α-methyl-m-tyrosine, yet depletion with reserpine was without effect. It appears that intact reserpine-resistant catecholamine stores are necessary for the anticonvulsant activity of chlordiazepoxide, and that 5-HT is in no way involved. Under these conditions, the activity of phenobarbitone was unaffected.

Date of Award	Dec 1969
Original language	English