The effect of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate excitatory amino acid antagonists on systemic cocaine-induced increases in extracellular dopamine was examined. The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor subtype antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and N-methyl-D-aspartate receptor antagonists, 2-amino-5-phosphonovalerate and dizocilpine, were infused via a microdialysis probe placed in the nucleus accumbens. The local infusion of 2-amino-5-phosphonovalerate (500 microM), dizocilpine (50 microM) and CNQX (100 microM), started 80 min before cocaine injection, significantly inhibited the cocaine-induced increase in extracellular dopamine. The CNQX blockade was dose-dependent with respect to both CNQX concentration infused and dose of cocaine administered. Simultaneous infusion of the two antagonists (500 microM 2-amino-5-phosphonovalerate and 100 microM CNQX) did not lead to further reductions in the effects of cocaine when compared to either antagonist alone. Our results suggest that both N-methyl-Daspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate subtypes of excitatory amino acid antagonist receptors may contribute to the stimulatory effect of cocaine on extracellular dopamine in the nucleus accumbens.