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The interactions between N-methyl-d-aspartate (NMDA) and D₁ dopamine receptors in the rat prefrontal cortex were examined using whole-cell recordings from pyramidal neurons. The effects of NMDA, the D₁ agonist SKF38393, or both compounds combined were tested on measures of cell excitability. Both NMDA (10–100 μM) and SKF38393 (5–10 μM) independently increased the number of spikes and decreased the latency of the first spike evoked by intracellular depolarizing current pulses. Combining low doses of NMDA (5 μM) and SKF38393 (2 μM) resulted in a marked increase of cell excitability. This synergism was blocked by SCH23390, protein kinase A (PKA) inhibitors, and the Ca²⁺ chelator BAPTA, and reduced by nifedipine. These results indicate the presence of a dopamine– glutamate interaction in the prefrontal cortex at the postsynaptic level, by which D₁ dopamine receptors may maintain …