The tissue response after brain damage implicates the cellular “activation” of astrocytes and microglia. This glial response is referred as reactive gliosis. Using immunohistochemical markers, we have analyzed the neuronal and glial response to some neurotoxic-induced lesions. We have compared the effects of two glutamate analogs, AMPA and kainic acid, with those of traumatic injury. Our data showed that the time-course of appearance, the relative contribution of and the behavior of reactive astrocytes and microglial cells were clearly different after AMPA or kainic acid administration. The immunoreactivity associated with microglia response, with respect to the immunoreactivity associated with reactive astrocytes, was higher after AMPA damage than after kainic acid treatment. In both cases, however, glial cells were more abundant than after traumatic lesions. Interestingly, the CA1 pyramidal neurons affected by AMPA and some cortical neurons affected by traumatic injury responded with an overexpression of amyloid precursor protein, whereas no neuronal response was detected after the kainic acid treatment. Our data suggest that the gliotic response is highly specific to the type of insult and heterogeneous depending on the brain area affected. © 1996 Wiley-Liss, Inc.