Dynorphin A (1-17) is an endogenous opioid peptide that is antinociceptive at physiological concentrations, but in excess can elicit a number of pathological effects. Both kappa-opioid and N-methyl-D-aspartate receptor antagonists modulate dynorphin toxicity, suggesting that dynorphin is acting directly or indirectly through these receptor types. We found in spinal cord neurons that the neurotoxic effects of dynorphin A and several dynorphin-derived peptide fragments are largely mediated by N-methyl-D-aspartate receptors. Despite these findings, aspects of dynorphin A toxicity could not be accounted for by opioid or N-methyl-D-aspartate receptor mechanisms. To address this issue, neurons enriched in kappa-opioid, N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors were isolated from embryonic day-15 mouse striata and the effects of extracellularly administered dynorphin A (1-17) and (13-17) on neuronal survival were examined in vitro. Unlike spinal cord neurons, N-methyl-D-aspartate receptors mature later than alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors in striatal neurons, thus providing a strategy to elucidate non-N-methyl-D-aspartate receptor-mediated mechanisms of toxicity. Time-lapse photography was used to repeatedly follow the same neurons before and during experimental treatments. Dynorphin A (1-17 or 13-17; 10 microM) caused significant neuronal losses after 48 to 72 hours versus untreated controls. Dynorphin A or A (13-17) toxicity was unaffected by the opioid receptor antagonist naloxone (10 microM) or by dizocilpine (10 microM). In contrast, the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline- 2,3-dione (10 microM) significantly attenuated only dynorphin A (1-17)-induced neuronal losses and not that induced by dynorphin A (13-17). Dynorphin A (1-17) toxicity was accompanied by a proportional loss of R2 and R3 subunits of the AMPA receptor complex, but not non-N-methyl-D-aspartateR1, expressing neurons and was mimicked by the ampakine 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine. Although it is unclear whether dynorphin A activates alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors directly or indirectly via glutamate release, our culture conditions do not support glutamate retention or accumulation. Our findings suggest that dynorphin A (1-17) can exert toxic effects on striatal neurons via an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor mechanism.