The present experiments were designed to further examine the hypothesis that receptor subtype determines the direction of dopamine's (DA) ability to modulate neostriatal neuronal responses. We have reported that DA potentiates responses mediated by activation of N-methyl-d-aspartate (NMDA) receptors, but attenuates responses mediated by activation of non-NMDA receptors in neocortex [Cepeda et al. (1992b) Synapse, 11:330-341] and neostriatum [Cepeda et al. (1993) Proc. Natl. Acad. Sci. U.S.A., 90:9576-9580]. In these studies, responses to excitatory amino acids (EAAs) were evoked by microphoretic application of agonists. The present studies examined whether this differential modulation also applies to components of synaptic responses evoked by electrical stimulation of neostriatal afferents and mediated by activation of specific subtypes of EAA receptors. Using brain slices, the actions of DA and its receptor specific agonists on components of neostriatal synaptic responses that were mediated either by NMDA or non-NMDA receptors were assessed. Responses mediated by NMDA receptors were potentiated by DA while those mediated by non-NMDA receptors were attenuated. These findings provide further support for the hypothesis that the direction of modulatory action of DA is determined by the specific subtype of EAA receptor activated. In addition, the enhancement of NMDA receptor-mediated responses was mimicked by application of SKF 38393, a D1 receptor agonist. Quinpirole, a D2 receptor agonist, consistently attenuated responses mediated by activation of non-NMDA receptors. Thus, the complex modulatory actions of DA are dependent upon combinations of co-activation of specific subtypes of EAA and DA receptors. These findings are of clinical relevance since the actions of DA and EAAs have been implicated in neurological and affective disorders.