Increased levels of dopamine have been associated with schizophrenia and mania; conversely, decreased levels of dopamine are associated with depression. Since the main mechanism for the termination of dopamine's pharmacological action is by re-uptake into the presynaptic cell, the speed of dopamine transport dramatically influences the concentration of dopamine present in the synaptic cleft, which in turn could determine brain disorders. Our preliminary studies have found that ATP can stimulate dopamine transport in rat synaptosomal preparation. We have also observed this ATP-regulated moiety of the dopamine uptake system when tested in PC12 cells. The large magnitude of ATP stimulation suggests that this dopamine uptake pathway may be important in the etiology and treatment of brain disorders. In order to test the relevance of ATP-stimulated dopamine uptake, we tested the effect of lithium salts on this system. Lithium chloride, one of the first drugs used in the treatment of mania, has become one of the most important agents utilized for the treatment of manic-depression and many schizoeffective disorders. Unfortunately, despite all efforts that have been made to explain lithium's mode of action, a clear cut biochemical mechanism has not been defined. We have found that lithium chloride, at therapeutic levels, is able to stimulate the ATP-regulated component of the dopamine uptake system by 49%. The further enhancement of dopamine re-uptake by lithium ions is consistent with its therapeutic effect. It is suggested that any substance that facilitates dopamine re-uptake could be of great importance in defining a useful treatment for mania and schizophrenia, as well as depression.