The present study was designed to investigate the role of dopamine in the locomotor stimulant response produced by the bilateral administration of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) into the nucleus accumbens. The hypermotility produced by lower doses of AMPA (up to 0.25 microgram) was inhibited by either SCH23390 or sulpiride, a D1 and D2 receptor antagonist, respectively. The locomotor response to a higher dose of AMPA (0.5 microgram) was greater than the maximum response to intra-accumbal injection of amphetamine and was significantly inhibited only when both the D1 and D2 antagonists were administered together. Alpha-Methyl-p-tyrosine inhibited the locomotor response to AMPA (0.5 microgram), and this inhibition was reversed by the co-injection of AMPA with either SKF38393, a D1 agonist, or quinpirole, a D2 agonist, at doses which were ineffective in the absence of AMPA. AMPA when infused into the nucleus accumbens produced an increase in extracellular dopamine, suggesting that AMPA can enhance dopamine efflux. The injection of AMPA into the nucleus accumbens significantly increased the DOPAC/dopamine ratio, which is different from the decrease in ratio reported for amphetamine. These data suggest that the stimulation of locomotor activity by intra-accumbal AMPA may be the result of an enhancement in dopamine efflux as well as a change in the response to dopaminergic receptor activation.