It has been reported that several uncompetitive NMDA receptor ion channel blocking agents (phencyclidine, ketamine, dizocilpine, dextrorphan) cause transient reversible vacuolation in neurons in the posterior cingulate cortex of rats. Similar effects have also been observed with competitive glutamate antagonists such as CPP, CGS 19755 and CGP 37849. This transient morphological change has been noted to be coincident anatomically with brain regions showing hypermetabolism after administration of uncompetitive NMDA receptor ion channel blockers and competitive glutamate antagonists. These results therefore indicate that the functional consequences of NMDA receptor blockade with competitive glutamate and uncompetitive channel antagonists are ultimately the same. These changes do not appear to be a prelude to irreversible damage except after relatively high doses of the receptor ion channel antagonists but they have given rise to concern over the safety in use of NMDA antagonists as neuroprotective agents. In contrast, vacuolation has not yet been demonstrated with agents acting at the glycine (L-687,414) or polyamine (eliprodil) modulatory sites of the NMDA receptor complex suggesting that agents acting at these sites may have a greater potential therapeutic window.