Chronic (14 daily injections) treatment of mice with the prototypic tricyclic antidepressant imipramine significantly alters ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. These effects were compared to a chronic regimen of 1-aminocyclopropanecarboxylic acid, a high-affinity partial agonist at strychnine-insensitive glycine receptors which mimics the effects of imipramine in preclinical models predictive of antidepressant action. Changes in the NMDA receptor complex after chronic, but not acute treatment with imipramine were manifested as 1) a reduction in the potency of glycine to inhibit [3H]5,7-dichlorokynurenic acid binding to strychnine-insensitive glycine receptors; 2) a decrease in the proportion of high-affinity glycine sites inhibiting [3H]CGP 39653 binding to NMDA receptors; and 3) a decrease in basal [3H]MK-801 binding (under nonequilibrium conditions) to sites within NMDA receptor-coupled cation channels which was reversible by the addition of glutamate. These effects were observed in cerebral cortex, but not in hippocampus, striatum or basal forebrain. Chronic treatment with 1-aminocyclopropanecarboxylic acid resulted in changes which paralleled those of imipramine on ligand binding to the NMDA receptor complex, but the reduction in basal [3H]MK-801 binding did not achieve statistical significance. These findings indicate that adaptive changes in the NMDA receptor complex could be a feature common to chronic treatment with structurally unrelated antidepressants.