Amitriptyline prevents N-methyl-D-aspartate (NMDA)-induced toxicity, does not prevent NMDA-induced elevations of extracellular glutamate, but augments kainate-induced elevations of glutamate.

The effect of amitriptyline on kainate- and N-methyl-D-aspartate (NMDA)-induced toxicity and release of amino acids from cerebellar granule neurons was studied. The ED50 for amitriptyline, imipramine, and nortriptyline protection against NMDA-induced toxicity was 6.9, 6.5, and 1.3 microM, respectively. None of these compounds protected against kainate-induced toxicity. Even though amitriptyline was protective against NMDA-induced toxicity, it had no effect on the NMDA-induced increase in extracellular levels of glutamate or aspartate from these cells, indicating a dissociation between NMDA receptor activation (as indicated by glutamate content elevations) and NMDA-induced toxicity. However, kainate and quisqualate treatment resulted in elevations of glutamate and taurine levels that were further augmented in the presence of 25 microM amitriptyline. These findings confirm the reports of others that tricyclic antidepressants have neuroprotective effects related to the NMDA receptor and expand on these reports by showing that even though there is protection against toxicity, the NMDA receptor is nevertheless activated, suggesting an involvement of these compounds at sites removed from the receptor. Furthermore, this is the first report showing an interaction of tricyclic antidepressants with the function of non-NMDA receptors.