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

The Pharmacogenomics Journal volume 6, pages 413–420 (2006)Cite this article

A Retraction to this article was published on 17 October 2017

Abstract

Chronic lithium and carbamazepine, which are effective against mania in bipolar disorder, decrease the activity of cytosolic phospholipase A2 (cPLA2) 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 cPLA2 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 cPLA2 protein, phosphorylated cPLA2, 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 cPLA2 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 cPLA2 gene expression post-transcriptionally by increasing cPLA2 mRNA stabilization. Chronic fluoxetine's effect on cPLA2 expression was opposite to the effect reported with chronic lithium or carbamazepine administration, and may be part of fluoxetine's mode of action.

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Abbreviations

AP-1:

activator protein-1

AP-2:

activator protein-2

AUF:

AU-rich element/poly(U)-binding/degradation factor

cPLA2:

cytosolic phospholipase A2

iPLA2:

calcium-independent phospholipase A2

MAPK:

mitogen-activated protein kinase

PEA3:

polyoma enhancer element 3

NF-κB:

nuclear factor kappa B

sPLA2:

secretory phospholipase A2

SSRI:

selective serotonin reuptake inhibitor

5-HT:

serotonin

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, NIA.

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  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    J S Rao, R N Ertley, H-J Lee, S I Rapoport & R P Bazinet

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Rao, J., Ertley, R., Lee, HJ. et al. Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex. Pharmacogenomics J 6, 413–420 (2006). https://doi.org/10.1038/sj.tpj.6500391

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