CHRONIC IMIPRAMINE ADMINISTRATION AMPLIFIES THE SEROTONIN(2A) RECEPTOR-INDUCED INTRACELLULAR CA2-CELLS THROUGH A CALMODULIN-DEPENDENT PATHWAY( MOBILIZATION IN C6 GLIOMA)

In the present study, we examined whether chronic exposure of C6BU-1 c ells to 100 nM of several different types of antidepressants directly influences serotonin(2A) (5-HT2A) receptor-stimulated intracellular Ca 2+ mobilization, Imipramine, desipramine, clomipramine, and maprotilin e amplified the 5-HT response at 18, but not at 2, h, Imipramine incre ased the maximum response to 5-HT without altering the EC50 of the dos e-response curve, This effect was time dependent and cycloheximide blo cked the maximal induction, suggesting an essential role for protein s ynthesis in this process. Previous exposure of the cells to thrombin o r isoproterenol did not influence 5-HT2A receptor function and pretrea tment with imipramine did not alter the thrombin- or bradykinin-induce d Ca2+ mobilization, which indicates that the effects of imipramine ap pear to be specific to the 5-HT2A receptor. The effect of imipramine w as potently suppressed by a calmodulin antagonist, W-13, in a dose-dep endent manner. Furthermore, this amplified 5-HT response was blocked b y KN-93, but not by H-7, Taken together, these results suggest that im ipramine has a modulatory effect on the 5-HT2A receptor-coupled intrac ellular Ca2+ in C6 cells through a calmodulin-dependent pathway, possi bly involving Ca2+/calmodulin kinase activation.