Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex.

Chronic lithium and carbamazepine, which are effective against mania in bipolar disorder, decrease the activity of cytosolic phospholipase A(2) (cPLA(2)) and the turnover rate of arachidonic acid in phospholipids in rat brain. Assuming that stages of bipolar disorder are related to brain arachidonic acid metabolism, we hypothesized that drugs effective in depression would increase cPLA(2) activity. To test this hypothesis, adult male CDF-344 rats were administered fluoxetine (10 mg/kg intraperitoneally (i.p.) or saline (control) (i.p.) chronically for 21 days. Frontal cortex cPLA(2) protein, phosphorylated cPLA(2), activity and mRNA levels were increased after chronic fluoxetine. Transcription factors (activator protein-1, activator protein-2, glucocorticoid response element, polyoma enhancer element-3 and nuclear factor-kappa B) that are known to regulate cPLA(2) gene expression were not significantly changed by chronic fluoxetine, but nuclear AU-rich element/poly(U)-binding/degradation factor-1 RNA-stabilizing protein was increased significantly. The results suggest that chronic fluoxetine increases brain cPLA(2) gene expression post-transcriptionally by increasing cPLA(2) mRNA stabilization. Chronic fluoxetine's effect on cPLA(2) expression was opposite to the effect reported with chronic lithium or carbamazepine administration, and may be part of fluoxetine's mode of action.