Imipramine stimulates phospholipase C activity in rat brain

Abstract

We previously demonstrated that antidepressant drugs (ADs) cause Ca 2+ release from inositol 1,4,5-trisphosphate-sensitive Ca 2+ stores in cultured neurons of rat frontal cortex. The present study examines the mechanism by which tricyclic ADs activate phospholipase C (PLC) in rat frontal cortex. Using an exogenous substrate to measure PLC activity, we demonstrated that a tricyclic AD, imipramine, stimulated PLC activity of the frontal cortex membrane in a concentration-dependent manner. Two tricyclic ADs, desipramine and amitriptyline, also stimulated PLC activity, while Li + or pargyline had no effect on PLC activity. Although imipramine did not activate PLC in the membrane in the absence of Ca 2+, imipramine synergistically activated PLC in the presence of Ca 2+. This result indicates that the mechanism of PLC activation by imipramine is different from its activation by Ca 2+. Imipramine stimulated PLC activity in the cytosol of rat frontal cortex as well as in the membrane. Preincubation of the cytosol with anti-PLC- β 1 antibody prevented the imipramine-mediated activation of PLC. However, preincubation with anti-PLC- γ 1 or anti-PLC- δ 1 did not prevent activation of PLC. These results suggest that imipramine activates PLC- β 1 directly without receptor or guanine nucleotide binding protein mediation.