The facilitated activity of -methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li, which suppresses the sodium-calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li]s of 0.5-1 mM cause an increase in ATL and DES ICs of ~10 folds and ~4 folds, respectively, for the Ca-dependent NMDAR inhibition. The Ca-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li. This Ca-dependent interplay between Li, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li]s may weaken ATL and DES effects during combined therapy. The data suggest that Li, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug-drug or ion-drug interaction when these medicines are used together therapeutically.