Inhibition of tryptophan hydroxylase: neurochemical action of catecholamide seizure-inducing agent.
H13/04, an audiogenic seizure-inducing catecholamide, has previously been demonstrated to decrease the accumulation of 5-hydroxytryptophan (5-HTP), while increasing the accumulation of dihydroxyphenylalanine (DOPA) after aromatic acid decarboxylase inhibition in vivo. The present study examined the effect of H13/04 on intracellular storage, release, and metabolism of serotonin (5-HT) and noradrenaline (NA) in vitro in order to differentiate between the primary effects of the drug and possible secondary effects due to neurotransmitter interaction. H13/04 had not effect on NA synthesis by brain minces from C57BL/6 mice, but did have a marked effect on [P3H]5HT synthesis from [3H]tryptophan in mouse brain minces. H13/04 was subsequently shown to competitively inhibit tryptophan hydroxylase. The data presented in this study indicate that the primary action of H13/04 on biogenic amines is to decrease the synthesis rate of 5-HT by competitive inhibition of tryptophan hydroxylase. The lack of any effect on NA in vitro is consistent with the hypothesis that the primary biochemical action of the drug is on the 5-HT system and that the action on NA in vivo is an indirect effect possibly secondary to the inhibition of 5-HT synthesis.
D000161:Acoustic Stimulation; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013687:Telencephalon / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors*
D000577:Amides; D002396:Catechols; D012701:Serotonin; C009975:H 1304; D014365:Tryptophan Hydroxylase; D009638:Norepinephrine