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Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

Molecular Psychiatry volume 13, pages 585–596 (2008)Cite this article

Abstract

Bipolar disorder is a major medical, social and economic burden worldwide. However, the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review studies using a neuropharmacological approach in unanesthetized rats, combined with kinetic, biochemical and molecular biology techniques, showing that chronic administration of three Food and Drug Administration-approved mood stabilizers (lithium, valproate and carbamazepine) at therapeutically relevant doses, selectively target the brain arachidonic acid (AA) cascade. Whereas chronic lithium and carbamazepine decrease the binding activity of activator protein-2 and in turn the transcription, translation and activity of its AA-selective calcium-dependent phospholipase A2 gene product, valproate appears to be a non-competitive inhibitor of long-chain acyl-CoA synthetase. The net overlapping effects of the three drugs are decreased turnover of AA but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E2. Although these observations support the hypothesis proposed by Rapoport and colleagues that the AA cascade is a common target of mood stabilizers, this hypothesis is not necessarily exclusive of other targets. Targeting the AA cascade with drugs or diet may be a useful therapeutic approach in bipolar disorder, and examining the AA cascade in patients might help in better understanding the disease.

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Acknowledgements

Drs Mireille Basselin and Francesca Bosetti are thanked for critically reviewing the paper. This study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (JSR, H-JL, SIR and RPB) and a grant from the Natural Sciences and Engineering Research Council of Canada (RPB).

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

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

  2. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    R P Bazinet

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  1. J S Rao
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Correspondence to R P Bazinet.

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Rao, J., Lee, HJ., Rapoport, S. et al. Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?. Mol Psychiatry 13, 585–596 (2008). https://doi.org/10.1038/mp.2008.31

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  • DOI: https://doi.org/10.1038/mp.2008.31

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