NMDA stimulated the release of endogenous or tritiated dopamine from rat striatal slices and tritiated norepinephrine from cortical and hippocampal slices. The putative polyamine antagonists ifenprodil and SL 82.0715 inhibited [3H]norepinephrine release from cortical and hippocampal slices but enhanced the basal efflux of endogenous and tritiated dopamine from striatal slices. Incubation of striatal slices in a calcium-free buffer did not ameliorate these effects suggesting that the increase in dopamine efflux was not due to a calcium-dependent release process. Superfusion of striatal slices with 10 microM of either ifenprodil, cocaine, or amphetamine resulted in a significant release of tritiated dopamine which was reversed when the slices were again superfused with non-drug-containing buffer. The release observed in the presence of 10 microM ifenprodil (7-fold increase over basal) was intermediate between that observed for cocaine (3-fold increase) and amphetamine (12-fold increase). Both ifenprodil and SL 82.0715 also blocked the uptake of [3H]dopamine into striatal synaptosomes with IC50 values of approximately 1.5 microM. This was again intermediate between the values obtained for cocaine (0.43 microM) and amphetamine (4.2 microM). These results suggest that ifenprodil and its analog SL 82.0715 may act as indirect dopamine agonists by both blocking presynaptic dopamine uptake and by directly increasing the basal efflux of dopamine.