Antimanic therapies target brain arachidonic acid signaling: Lessons learned about the regulation of brain fatty acid metabolism

Bipolar disorder is a major medical, social and economic burden worldwide. However, the biochemical basis of the disorder and the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review how combining a kinetic approach to studying the turnover of fatty acids within brain phospholipids of unanesthetized rats along with chronic administration of antimanic drugs (lithium, valproate and carbamazepine) at therapeutically relevant doses, shows that the brain arachidonic acid cascade is a common target of these drugs. The overlapping effects of the three drugs are decreased turnover of arachidonic acid but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E2. Whereas lithium and carbamazepine target the transcription of the arachidonic acid-selective calcium-dependent cytosolic phospholipase A2, valproate is a non-competitive inhibitor of an arachidonic acid-selective acyl-CoA synthetase. Two potential models of bipolar disorder, chronic N-methyl-d-aspartate and n-3 polyunsaturated fatty acid deprivation, opposite to the antimanic drugs, increase the turnover and markers of the arachidonic acid cascade in rat brain. These observations support the hypothesis proposed by Rapoport and colleagues that the arachidonic acid cascade is a common target of mood stabilizers and that by targeting substrate-specific enzymes the turnover of individual fatty acids can be regulated within the brain.