High Concentrations of Tricyclic Antidepressants Increase Intracellular Ca2+ in Cultured Neural Cells

We examined the effect of tricyclic antidepressants on intracellular Ca²⁺ signalling in cultured cells of neuronal and glial origin. High concentrations of amitriptyline and desipramine increased the intracellular Ca²⁺ in PC-12 and U-87 MG cells. In PC-12 cells amitriptyline induced a biphasic rise in intracellular Ca²⁺. A rapid and transient increase due to release of Ca²⁺ from intracellular pools was followed by sustained elevation of Ca²⁺]_i due to influx from the extracellular medium. Desipramine evoked the Ca²⁺ release from intracellular pools but the influx of Ca²⁺ was not elicited. In U-87 MG cells both the drugs induced Ca²⁺ release from intracellular pools, however amitriptyline also induced a transient influx of Ca²⁺. To delineate the mechanisms involved in mobilization of Ca²⁺ by the drugs pharmacological agents that inhibit IP₃ formation in cells and Ca²⁺ channel blockers were used and changes in Ca²⁺]_i and membrane potential were monitored. The results show that both the drugs release Ca²⁺ from IP₃ sensitive pools by activation of phospholipase C and amitriptyline in addition activates a non specific cation channel in the plasma membrane of cells. Paradoxically at relatively lower concentrations (< 50 M) amitriptyline and desipramine inhibited the Ca²⁺ signal induced by adenosine triphosphate in both the cell types. Our data demonstrate that tricyclic antidepressants at different doses may have inhibitory or stimulatory effects on cellular Ca²⁺ signalling.