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 microM) 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.