Large amounts of zinc are endogenously present in synaptic vesicles of mammalian central excitatory boutons, and are likely released during synaptic activity; transient elevations in extracellular zinc concentration exceeding several hundred micromolar may accompany intense neuronal excitation. Exposure of mature cortical cell cultures, in mice, to similar concentrations of zinc for several minutes resulted in widespread neuronal injury; the extent of injury was dependent on both the concentration of zinc, and the length of exposure. Quantitative neuronal cell counts suggested an approximate neurotoxic ED50 of 600 microM for a 15 min zinc exposure, and 225 microM for an 18-24 h exposure. High zinc concentrations or long exposure times resulted in the addition of glial injury to the neuronal injury; this glial injury could also be demonstrated in neuron-free glial cell cultures, and hence likely represented a direct effect of zinc rather than a consequence of neuronal injury. Neurons in immature cultures were relatively resistant to zinc-induced injury, suggesting that neuronal vulnerability to zinc increases with maturation in vitro. An early event associated with toxic exposure to zinc was gross neuronal swelling. This swelling was dependent on the presence of extracellular sodium, and, interestingly, could be delayed by the continued presence of zinc itself. Zinc-induced neuronal cell loss, however, occurred even when both sodium and calcium were absent during the exposure to zinc. The present results provide direct evidence that zinc might be a relatively potent, rapidly acting neurotoxin, and somewhat less potent gliotoxin, in the mammalian central nervous system. We suggest that zinc should be included on the growing list of endogenous toxins which may be involved in the acute pathogenesis of central neuronal, and possibly glial, cell loss in some disease states.