Acromelic acid, a kainate derivative of natural origin, markedly increased intracellular Ca2+ concentration ([Ca2+]i) in cultured rat spinal neurons in a concentration dependent manner; the half effective concentration (EC50) was 1.3 microM. Acromelic acid was more potent in increasing [Ca2+]i than any other glutamate receptor agonists tested, and the rank order of the activity was as follows: acromelic acid > alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) > kainate > N-methyl-D-aspartate (NMDA) > L-glutamate. Acromelic acid did not increase the [Ca2+]i in a Ca(2+-)free medium. 2,3-Dihydroxy-9-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX) completely inhibited the [Ca2+]i increase induced by acromelic acid. These results suggest that the [Ca2+]i increase was not through Ca2+ mobilization from intracellular stores but due to Ca2+ influx mediated by the activation of non-NMDA receptors. Acromelic acid increased the [Ca2+]i in rat hippocampal neurons as well; however, the EC50 (6 microM) was considerably higher than that in spinal neurons. The marked increase of [Ca2+]i in cultured spinal neurons would explain, at least in part, the earlier findings that systemic administration of acromelic acid causes selective degeneration confined to lower spinal interneurons.