Drugs with NMDA-antagonist properties have multiple uses such as animal model of psychotic disorders, anesthetics, and drugs of abuse. In animals, high doses of NMDA antagonists induce neurodegeneration in retrosplenial cortex (RSC) but their mechanism remains unclear. Here, to test if an imbalance of synaptic inhibition and excitation would mediate the neurodegenerative effect of MK801 (a selective NMDA-antagonist), the participation of GABA-A, NMDA and AMPA/KA receptors were evaluated. Female adult rats were administered intraperitoneally with 2,5 mg/kg of MK801 and, locally in RSC, with muscimol (GABA-A agonist), DNQX (AMPA/KA antagonist), NASPM (calcium permeable AMPA/KA antagonist) and MK801 at several times (0.5, 5, 10, 24 hours) post systemic MK801 administration. Neuronal death was evaluated 48 hours after MK801 injection by fluoro jade-b and amino-cupric-silver techniques. The results showed that intra-RSC administration of muscimol, DNQX and NASPM (but not MK801) significantly decreased the MK801-induced neuronal death, even when applied ten hours later. The data suggest that a prolonged (more than 10 hours) GABA-A hipofunction and/or AMPA/KA hiperfunction are involved in the mechanism of NMDA antagonists induced neurodegeneration.