¹Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

Correspondence: Dr Y Dwivedi, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA. Tel: +1 312 413 4557; Fax: +1 312 355 3857; E-mail: ydwivedi@psych.uic.edu

Received 1 July 2004; Revised 9 September 2004; Accepted 28 September 2004; Published online 10 November 2004.

Abstract

PI-PLC, a critical enzyme of the phosphoinositide (PI) signaling pathway, mediates many physiological functions in the brain, including cellular plasticity. Stress-induced learned helplessness (LH) in animals serves as a model of behavioral depression. Recently, we observed that repeated stress prolongs the duration of LH behavior in rats, enabling us to compare neurobiologic abnormalities in acute and chronic depression. Here we examine whether LH behavior is associated with alterations in phospholipase C (PLC), and whether repetition of inescapable shock has similar or dissimilar effects on PLC to those of the single-stress paradigm. Rats were exposed to inescapable shock either once on day 1, or twice, on days 1 and 7. Rats were tested for escape latency on days 2 and 4 after day 1 inescapable shock or on days 2, 8, and 14 after day 1 and 7 inescapable shock. PI-PLC activity and mRNA and protein expression of three different PLC isozymes were determined in the frontal cortex and hippocampus. Higher escape latencies were observed in LH rats tested on day 2 after single inescapable shock and on day 14 after repeated inescapable shock. Single inescapable shock reduced PI-PLC activity in the frontal cortex and hippocampus of LH rats. On the other hand, repeated inescapable shock not only reduced PI-PLC activity in these brain areas of LH rats but also selectively decreased the expression of PLC ₁ and PLC ₁ isozymes. Our results suggest different responsiveness at the level of PI-PLC after single vs repeated stress, and that reductions in PLC may be critical in the pathophysiology of depression and other stress-related disorders.