Agents effective against mania in bipolar disorder are reported to decrease turnover of arachidonic acid (AA) in phospholipids and expression of calcium-dependent AA-selective cytosolic phospholipase A(2) (cPLA(2)) in rat brain. In contrast, fluoxetine, an antidepressant that is reported to switch bipolar depressed patients to mania, increases cPLA(2) expression and AA turnover in rat brain. We therefore hypothesized that antidepressants that increase switching to mania generally increase cPLA(2) and AA turnover in brain. To test this hypothesis, adult male CDF-344 rats were administered imipramine and bupropion, with reported high and low switching rates, respectively, at daily doses of 10 and 30 mg kg(-1) i.p., respectively, or i.p. saline (control) for 21 days. Frontal cortex expression of different PLA(2) enzymes and AA turnover rates in brain when the rats were unanesthetized were measured. Compared with chronic saline, chronic imipramine but not bupropion significantly increased cortex cPLA(2) mRNA activity, protein and phosphorylation, expression of the cPLA(2) transcription factor, activator protein-2alpha (AP-2alpha) and AA turnover in phospholipids. Protein levels of secretory phospholipase A(2), calcium-independent phospholipase A(2), cyclooxygenase (COX)-1 and COX-2 were unchanged, and prostaglandin E(2) was unaffected. These results, taken with prior data on chronic fluoxetine in rats, suggest that antidepressants that increase the switching tendency of bipolar depressed patients to mania do so by increasing AA recycling and metabolism in brain. Mania in bipolar disorder thus may involve upregulated brain AA metabolism.