In previous experiments, we have shown that antidepressants such as desipramine (DMI) can induce axonal regeneration of noradrenergic locus coeruleus neurons. In this article, we suggest that phospholipase A2 is involved in the molecular mechanism of the antidepressant-induced regeneration of brain noradrenergic axons. The effects of the PLAB inhibitors, mepacrine (MEP) or 4-bromphenacyl bromide (BPB), upon the DMI-induced regeneration of noradrenergic axons in the rat cerebral cortex were assessed by either histofluorescence or immunohistochemistry using an antibody to dopamine-beta-hydroxylase. Symmetrical sites of the frontal cortex in both hemispheres were pretreated with 6-hydroxydopamine (6-OHDA). Then, the same cortical site of one hemisphere was infused with DMI by means of osmotic minipumps for more than 2 weeks, while the corresponding cortical site of the other hemisphere was infused with DMI plus MEP or BPB. It was found that the PLAB inhibitors could attenuate the DMI-induced regeneration of noradrenergic axons. Thus, if axonal retraction or degeneration of brain noradrenergic neurons is involved in the pathogenesis of clinical depression, elucidating the malfunction of the PLAB systems may provide substantial evidence to aid in our understanding of the cause of depression at the molecular level. o 1994 Wiley-Liss, Inc.