Dopamine-NMDA Receptor Interactions: Twenty Years Later

activation of D1 receptors potentiated glutamate responses, in particular those mediated by NMDA receptors, whereas activation of D2 receptors attenuated glutamate responses, in particular those mediated by AMPA receptors [2] . At the time, the prevailing wisdom was that DA acted as an inhibitory neurotransmitter to depress spontaneous or glutamate-induced firing, although there was evidence for mixed effects which were correctly attributed to different DA receptor subtypes. Thus, the idea that DA functioned as a classical inhibitory neurotransmitter, such as GABA, was challenged. In agreement, the current consensus is that DA acts as a modulator that alters the responses evoked by excitatory and inhibitory neurotransmitters. Further studies in our laboratory demonstrated the importance of the cAMP-PKA-DARPP-32 cascade in the induction of differential effects by DA in striatal medium-sized spiny neurons (MSNs) [3] . While modulation of voltage-gated currents by DA also played a role in the enhancement of NMDA currents [4] , modulation occured even when voltage-gated currents were blocked [3] . The most parsimonious hypothesis was that the interplay between ligandand voltage-gated currents was responsible for DA receptor-mediated differential effects. To complete the picture, we also demonstrated that DA exIntroduction