The data obtained in these studies show that the antidepressant activity of bupropion cannot be explained by its ability to inhibit MAO present in brain or to increase the release of biogenic amines from nerve endings, since the drug possesses neither of these properties. It is also unlikely that the weak properties of the drug as an inhibitor of dopamine uptake in brain can explain its antidepressant activity. It is clear, however, that dopamine neurons must be present for the CNS properties of bupropion to be manifested in animal models; at antidepressant doses of the drug, dopamine turnover is reduced in brain. Finally, the antidepressant properties of bupropion have been dissociated from down-regulation of postsynaptic beta-receptors. To our knowledge, bupropion is the first clinically effective antidepressant whose mechanism of action cannot be explained on the basis of alterations in either presynaptic events or postsynaptic receptor-mediated events in catecholamine or serotonin pathways. Thus, bupropion is a novel antidepressant whose mechanism of action must still be elucidated.