Alterations in microtubule-associated protein 2 (MAP2) immunoreactivity following lateral fluid-percussion (FP) brain injury were investigated in rats with survival times ranging between 10 min and 7 days. MAP2 immunoreactivity was profoundly diminished in the cortex and hippocampus ipsilateral to the site of injury by 10 min and remained diminished up to 7 days after injury. Nissl staining and silver impregnation histochemistry demonstrated a correlation between the loss of MAP2 and neuronal degeneration. The effect of excitatory amino acid receptor antagonism on MAP2 immunoreactivity was evaluated by administering kynurenate or buffer 15 min after FP injury. Administration of kynurenate significantly attenuated the loss of MAP2 observed in the cortex two weeks after injury when compared to buffer treated control animals (P < 0.02). We conclude that significant and prolonged cytoskeletal changes occur following lateral FP brain injury, and that these alterations can be attenuated by blocking excitatory amino acid receptors.