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 mu M, 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 similar to 10 folds and similar to 4 folds, respectively, for the Ca2+-dependent NMDAR inhibition. The Ca2+-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 Ca2+-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.

Automated summary

The facilitated activity of N-methyl-D-aspartate receptors promotes neuropathic pain, and the anti-NMDAR properties of amitriptyline and desipramine contribute to their analgetic effects. Intracellular lithium ions enhance NMDAR desensitization by suppressing the sodium-calcium exchanger, leading to analgesia. This study found that therapeutic concentrations of lithium ions enhance the inhibitory effects of amitriptyline and desipramine on NMDARs, likely through competition for the same molecular target.