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Chronic imipramine but not bupropion increases arachidonic acid signaling in rat brain: is this related to ‘switching’ in bipolar disorder?

Molecular Psychiatry volume 15, pages 602–614 (2010)Cite this article

Abstract

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 A2 (cPLA2) in rat brain. In contrast, fluoxetine, an antidepressant that is reported to switch bipolar depressed patients to mania, increases cPLA2 expression and AA turnover in rat brain. We therefore hypothesized that antidepressants that increase switching to mania generally increase cPLA2 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 PLA2 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 cPLA2 mRNA activity, protein and phosphorylation, expression of the cPLA2 transcription factor, activator protein-2α (AP-2α) and AA turnover in phospholipids. Protein levels of secretory phospholipase A2, calcium-independent phospholipase A2, cyclooxygenase (COX)-1 and COX-2 were unchanged, and prostaglandin E2 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.

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This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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  1. H-J Lee and H-W Kim: These authors contributed equally to this work.

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

    H-J Lee, J S Rao, L Chang, S I Rapoport & H-W Kim

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Lee, HJ., Rao, J., Chang, L. et al. Chronic imipramine but not bupropion increases arachidonic acid signaling in rat brain: is this related to ‘switching’ in bipolar disorder?. Mol Psychiatry 15, 602–614 (2010). https://doi.org/10.1038/mp.2008.117

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