1. Using the radioligand [3H]-MK801, we have examined drug interactions with the phencyclidine recognition site of the N-methyl-D-aspartate receptor. 2. The tricyclic antidepressants desmethylimipramine and imipramine inhibited [3H]-MK801 binding with IC50 values of 7.4 and 22.5 microM, respectively. Other related tricyclic antidepressants and neuroleptics were also effective but less potent. 3. Desmethylimipramine, imipramine and chlorimipramine slowed the dissociation rate of [3H]-MK801 in a similar manner to Zn2+. Phencyclidine and related compounds had no effect on the dissociation rate of [3H]-MK801. 4. Desmethylimipramine, imipramine and ketamine also prevented the Ca2+ influx into cultured cortical neurones of the rat produced by N-methyl-D-aspartate. 5. As the actions of tricyclic antidepressants in this system are not competitive with respect to N-methyl-D-aspartate, glycine or MK-801, and as they slow the dissociation of [3H]-MK801, we conclude that tricyclic antidepressants may be acting at the Zn2+ recognition site on the N-methyl-D-aspartate receptor.