A comparative study of the ability to block the amine pump was carried out on tricyclic antidepressants including dothiepin and northiaden in vivo. Dothiepin was found to prevent the 6-OHDA-induced depletion of cardiac noradrenaline but not the PCA-induced depletion of intracerebral serotonin. Northiaden, an active metabolite of dothiepin, also possessed the same ability with a greater potency than the parent drug. Neither compound affected the biosynthesis of catecholamines and indoleamine. However, neither dothiepin nor northiaden affected 5-HT uptake, as was also observed with imipramine and amitriptyline. These results suggest that the clinical efficacy of dothiepin may be due to inhibition of the amine pump, especially of the catecholamine uptake mechanism, which is qualitatively the same as for imipramine and amitriptyline.