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.