The mood-stabilizer lithium, when chronically administered to rats at therapeutic concentrations, has been shown to downregulate brain arachidonic acid (AA) turnover and total phospholipase A2 (PLA2) activity, as well as protein and mRNA levels of cytosolic cPLA2. These effects are accompanied by a decrease in cyclooxygenase (COX)-2 protein level, COX activity, and brain prostaglandin E2 (PGE2) concentration. The involvement of Ca2+-dependent secretory PLA2 (sPLA2) in the mechanism of action of lithium has not been investigated. The purpose of this study was to examine, whether the effect of lithium is selectively directed to cPLA2 or it also affects sPLA2 protein and enzyme activity and whether other AA metabolizing enzymes (5-lipoxygenase and cytochrome P450 epoxygenase) were also altered. Furthermore, to determine if the reduction of brain PGE2 concentration was due only to downregulation of COX-2 protein or if it also involves the terminal PGE synthase, we determined brain microsomal PGE synthase protein level. Male Fischer-344 rats were fed lithium chloride for 6 weeks, whereas, control rats were fed lithium-free chow under parallel conditions. We found that chronic lithium did not significantly change sPLA2 activity or protein level. 5-Lipoxygenase and cytochrome P450 epoxygenase protein levels were unchanged, as were levels of the terminal PGE synthase. These results indicate that the effect of lithium selectively involves the cPLA2/COX-2 pathway, which might be responsible for the therapeutic effect in bipolar disorder.