Chronic Imipramine Administration Amplifies the Serotonin2A Receptor-Induced Intracellular Ca2+ Mobilization in C6 Glioma Cells Through a Calmodulin-Dependent Pathway

In the present study, we examined whether chronic exposure of C6BU-1 cells to 100 nM of several different types of antidepressants directly influences serotonin, (5-HT 2A ) receptor-stimulated intracellular Ca 2+ mobilization. Imipramine, desipramine, clomipramine, and maprotiline amplified the 5-HT response at 48, but not at 2, h. Imipramine increased the maximum response to 5-HT without altering the EC 50 of the dose-response curve. This effect was time dependent and cycloheximide blocked the maximal induction, suggesting an essential role for protein synthesis in this process. Previous exposure of the cells to thrombin or isoproterenol did not influence 5-HT 2A receptor function and pretreatment with imipramine did not alter the thrombin- or bradykinin-induced Ca 2+ mobilization, which indicates that the effects of imipramine appear to be specific to the 5-HT 2A receptor. The effect of imipramine was potently suppressed by a calmodulin antagonist, W-13, in a dose-dependent manner. Furthermore, this amplified 5-HT response was blocked by KN-93, but not by H-7. Taken together, these results suggest that imipramine has a modulatory effect on the 5-HT 2A receptor-coupled intracellular Ca 2+ in C6 cells through a calmodulin-dependent pathway, possibly involving Ca 2+ /calmodulin kinase activation.