Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain.

To compare in vivo effects of eleven compounds of different classes of histamine H1-receptor antagonists (alcoholamines: diphenhydramine, carbinoxamine, and clemastine; ethylenediamines: mepyramine, tripelennamine, and clemizole; alkylamines: triprolidine and chlorpheniramine; piperazines: meclizine and homochlorcyclizine; phenothiazines: promethazine) on neuronal uptake of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT), the effects on the turnover of these monoamines were examined in the mouse brain, based on the alpha-methyl-p-tyrosine-induced depletion of DA and NA or probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The DA turnover was reduced remarkably by diphenhydramine, tripelennamine, and promethazine, and also significantly by chlorpheniramine, mepyramine, clemizole, and homochlorcyclizine, at doses used in the ordinary animal experiments. The 5-HT turnover was reduced markedly by mepyramine, tripelennamine, and chlorpheniramine. In contrast, the NA turnover was increased by promethazine and homochlorcyclizine, possibly due to their antagonistic effects on alpha-adrenoceptors. These results suggest that (1) the degree of inhibition of the uptake of DA and 5-HT by histamine H1-receptor antagonists is considerably different, (2) most H1-antagonists have little influence on NA uptake and some compounds enhance NA release, and that (3) carbinoxamine, clemastine, triprolidine, and meclizine have comparatively weak influences on monoamine metabolism. These effects on brain monoamine systems may be related to some central actions of histamine H1-receptor antagonists, such as an addiction to these compounds combined with opioids.