Journal
MOLECULAR PSYCHIATRY
Volume 13, Issue 6, Pages 585-596Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2008.31
Keywords
bipolar disorder; mood stabilizer; arachidonic acid; prostaglandin; phospholipase; cyclooxygenase
Funding
- Intramural NIH HHS Funding Source: Medline
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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 A(2) 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 E-2. 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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