Glutamatergic afferents from the neocortex constitute the major excitatory input to striatal medium-sized spiny neurons (MSNs). Glutamate's actions on MSNs are modulated by dopamine (DA) through D1 and D2 receptor families. Although D1 modulation of glutamate responses has been well-characterized, the contribution of postsynaptic D2 receptors to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses has not been studied extensively. We examined DA modulation of AMPA currents using whole-cell voltage-clamp recordings of MSNs acutely dissociated and in slices. In dissociated cells, the D2 agonist quinpirole (10 micro m) produced small and inconsistent effects on AMPA currents. The magnitude of the current, as well as its modulation by quinpirole, was related to the dendritic elaboration of the dissociated cell. Thus, quinpirole altered AMPA currents only slightly when few initial dendritic segments were present. The amplitude of the current was greater and quinpirole consistently decreased this current in dissociated cells displaying at least three primary dendrites and several secondary and tertiary dendrites. Cyclothiazide, a compound that prevents AMPA receptor desensitization, greatly increased AMPA currents. In the presence of cyclothiazide, quinpirole also consistently reduced AMPA currents. Finally, in slices, AMPA current amplitude was always reduced after application of quinpirole. Sulpiride, a D2 antagonist, prevented attenuation of AMPA currents in both acutely dissociated neurons and neurons in slices. These results provide evidence that AMPA currents are attenuated by DA via activation of postsynaptic D2 receptors. In addition, they indicate that the dendrites and/or the amplitude of the current are important variables for DA modulation of AMPA currents in MSNs.