Functional antagonists of the NMDA receptor complex are active in both preclinical behavioral paradigms sensitive to antidepressants (ADs) and in the chronic mild stress (CMS) animal model of depression. Chronic AD treatment induces adaptation of the NMDA receptor complex in naive rodents. Specifically, this adaptation is evident as a reduction in the potency of glycine to displace [ 3 H]5,7-dichlorokynurenic acid (5,7-DCKA) from the glycine recognition site and/or the reduction in the proportion of high affinity, glycine-displaceable [ 3 H]CGP-39653 binding to the glutamate recognition site of the NMDA receptor complex. These effects are not observed following chronic administration of structurally related non-AD treatments. We tested the hypothesis that animal models of depression would result in AD-reversible adaptation of the NMDA receptor complex. We now report that CMS results in the enhancement of the potency of glycine to displace [ 3 H]5,7-DCKA binding, which is reversible by chronic imipramine and citalopram treatment. These data support the hypothesis that depression is associated with dysfunction of the NMDA receptor complex.