We have investigated the effects of infusing the excitatory amino acid agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on extracellular levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rat striatum using in vivo microdialysis. AMPA (50-500 microM) caused a concentration-dependent increase in extracellular 5-HT, while having the converse effect on 5-HIAA. At the highest agonist dose the decrease in dialysate 5-HIAA was followed by a significant increase in this metabolite. Two hundred micromolar 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a competitive non-NMDA glutamate receptor antagonist, reversed the effects of a 100 microM AMPA on dialysate 5-HT and 5-HIAA. Co-infusion of AMPA with tetrodotoxin (TTX) abolished the effects of 100 microM AMPA, but only partially reversed the effect of 500 microM AMPA on 5-HT release. We have also investigated whether AMPA receptor desensitization, a well documented event, plays a role in AMPA receptor modulation of striatal 5-HT release. Diazoxide (500 microM), a drug which prevents AMPA receptor desensitization, failed to augment the effect of 100 microM AMPA on 5-HT release. Diazoxide alone significantly decreased 5-HT release, as did the drug cromakalim (100 microM), probably as a result of their common action as activators of ATP-dependent K+ channels. It is concluded that AMPA receptors play a role in regulating both 5-HT release and metabolism in rat striatum. However, AMPA receptor desensitization does not appear to play a role in this process in this structure.