Abstract The effect of antidepressant drugs of the imipramine type and of the antihistamine drugs chlorpheniramine and brompheniramine on the amine uptake-accumulation mechanism of the central noradrenaline (NA) and 5-hydroxytryptamine (5-HT) neurons were studied in vivo and in vitro in the rat. The in vitro experiments were performed on isolated nerve ending particles following the uptake and accumulation of tritiated NA and 5-HT in the presence of the psychoactive drugs in the incubation medium. The in vivo experiments were analyzed by a fluorescence histochemical method for NA and 5-HT and involved an examination of the effect of the psychoactive drugs on the uptake and accumulation of intraventricularly administered NA or 5-HT and of the accumulation of endogenously synthesized 5-HT aftei monoamine oxidase inhibition in rats pretreated with reserpine. The present results support the view that tertiary amines of the imipramine-type of drugs, such as amitriptyline, imipramine and chlorimipramine, which are well-known and frequently used antidepressant drugs, preferentially block 5-HT uptake in the central 5-HT neurons, whereas secondary amines of the imipramine tppe, such as desipramine, preferentially block NA uptake in the central NA neurons. Functional studies using the extensor and flexor reflex model to evaluate the influence on 5-HT and NA receptor activity, respectively, by the psychoactive drugs further support this view. Thus, the antidepressant action of these drugs may be related to their ability to increase 5-HT receptor activity by blocking 5-HT reuptake. The antihistamine drugs, chlorpheniramine and especially brompheniramine, were found to be very potent blockers of 5-HT uptake as revealed both chemically and functionally. They also had, in contrast to the imipramine-like drugs of the tertiary amine type, a potent blocking action on NA reuptake in the central NA neurons. Drugs with these properties may be of new importance in the management of mental depression.