Imipramine stimulates phospholipase C activity in rat brain.
We previously demonstrated that antidepressant drugs (ADs) cause Ca2+ release from inositol 1,4,5-trisphosphate-sensitive Ca2+ 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 Ca2+, imipramine synergistically activated PLC in the presence of Ca2+. This result indicates that the mechanism of PLC activation by imipramine is different from its activation by Ca2+. Imipramine stimulated PLC activity in the cytosol of rat frontal cortex as well as in the membrane. Preincubation of the cytosol with anti-PLC-beta 1 antibody prevented the imipramine-mediated activation of PLC. However, preincubation with anti-PLC-gamma 1 or anti-PLC-delta 1 did not prevent activation of PLC. These results suggest that imipramine activates PLC-beta 1 directly without receptor or guanine nucleotide binding protein mediation.
Fukuda
H
H
Department of Psychiatry and Neuroscience, Kure National Hospital, Hiroshima, Japan.
Nishida
A
A
Saito
H
H
Shimizu
M
M
Yamawaki
S
S
D000818:Animals; D000906:Antibodies; D001921:Brain; D002118:Calcium; D003600:Cytosol / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology*; D051381:Rats; D010738:Type C Phospholipases / Q000187:drug effects*
D000906:Antibodies; D010738:Type C Phospholipases; D007099:Imipramine; D002118:Calcium