The effect of various classes of excitatory amino acid agonists on the release of dopamine in the medial prefrontal cortex (PFC) of awake rats was examined using intracerebral microdialysis. Local infusion of 20 muM alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), through the microdialysis probe, produced a significant increase of more than twofold in extra-cellular levels of dopamine. Application of 100 microM AMPA increased these levels nearly 15 fold. The AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (50microM) blocked the increase in dopamine release produced by 20 microM AMPA. Local infusion of kainate at concentrations of 5 and 20 microM increased dopamine release by nearly 150 and 500%, respectively. Local application of CMQX (50 microM) before 20 microM kainate significantly attenuated the stimulatory effect of kainate on dopamine levels. In contrast to AMPA and kainate, infusion of N-methyl-D-aspartate (NMDA) at 20 or 100 microM did not increase dopamine release. In fact, a trend toward a decrease in dopamine release was evident after 100 microM NMDA. The present study indicates that the in vivo release of dopamine in the PFC is facilitated by AMPA and kainate receptors. This modulation is more profound than that previously reported in basal ganglia. The lack of an excitatory effect of NMDA is in agreement with recent reports that the NMDA receptor may inhibit indirectly dopaminergic neurotransmission in the PFC.