Calcium-Dependent Interplay of Lithium and Tricyclic Antidepressants, Amitriptyline and Desipramine, on N-methyl-D-aspartate Receptors

The facilitated activity of N-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 IC(50)s of ~10 folds and ~4 folds, respectively, for the Ca(2+)-dependent NMDAR inhibition. The Ca(2+)-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(2+)-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.