In order to examine whether antidepressants mediate their action by interacting with one of the key components of the phosphoinositide (PI) signaling pathway, i.e. PI-specific phospholipase C (PLC), and whether this represents a common mechanism of action of antidepressants, we determined the effects of antidepressants of various classes on PI-PLC activity and on the expression of PLC isozymes in rat brain. It was observed that chronic (21-day) but not acute (1-day) administration with desipramine (DMI), fluoxetine (FLX) and phenelzine (PHLZ), decreased PI-PLC activity in membrane and cytosol fractions of cortex and hippocampus. Similar changes were observed with alprazolam (ALP) and buspirone (BUS), who possess anxiolytic and antidepressant properties. On the other hand, an anxiogenic drug, metachlorophenylpiperazine (MCPP), increased PI-PLC activity in both membrane and cytosol fractions of cortex and hippocampus. The immunolabeling studies showed that all the antidepressants and anxiolytics that caused a decrease in PI-PLC activity also selectively decreased the protein levels of a specific isozyme of PLC, i.e. PLCβ1, in membrane and cytosol fractions of cortex and hippocampus, whereas MCPP increased the levels of this particular isozyme. These changes were accompained with changes in the mRNA levels of PLCβ1, as determined by quantitative RT-PCR. These antidepressants and anxiolytics did not cause significant changes in the expression of PLC δ1 or γ1 isozyme. Our results thus suggest that modulation of PI-PLC may be common to all classes of antidepressants, which in turn, may be associated with their mechanisms of action. © 2002 Elsevier Science Ltd. All rights reserved.