title: Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder?
abstract: Although lithium has been used therapeutically to treat patients with bipolar disorder for over 50 years, its mechanism of action, as well as that of other drugs used to treat bipolar disorder, is not agreed upon. In the present paper, I review studies in unanaesthetized rats using a neuropharmacological approach, combined with kinetic, biochemical and molecular biology techniques, demonstrating that chronic administration of three commonly used mood stabilizers (lithium, valproic acid and carbamazepine), at therapeutically relevant doses, selectively target the brain arachidonic acid cascade. Upon chronic administration, lithium and carbamazepine decrease the binding activity of activator protein-2 and, in turn, the transcription, translation and activity of its arachidonic acid-selective calcium-dependent phospholipase A(2) gene product, whereas chronic valproic acid non-competitively inhibits long-chain acyl-CoA synthetase. The net overlapping effects of the three mood stabilizers are decreased turnover of arachidonic acid, but not of docosahexaenoic acid, in rat brain phospholipids, as well as decreased brain cyclo-oxygenase-2 and prostaglandin E(2). As an extension of this theory, drugs that are thought to induce switching to mania, especially when administered during bipolar depression (fluoxetine and imipramine), up-regulate enzymes of the arachidonic acid cascade and turnover of arachidonic acid in rat brain phospholipids. Future basic and clinical studies on the arachidonic acid hypothesis of bipolar disorder are warranted.
authors.affiliation: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Room 306, FitzGerald Building, Toronto, Ontario, Canada. richard.bazinet@utoronto.ca
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bazinet
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D016718:Arachidonic Acid / Q000378:metabolism*; D001714:Bipolar Disorder / Q000188:drug therapy*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000077213:Lamotrigine; D018020:Lithium Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000077236:Topiramate; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014635:Valproic Acid / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D000928:Antidepressive Agents; D018020:Lithium Compounds; D014227:Triazines; D000077236:Topiramate; D016718:Arachidonic Acid; D005632:Fructose; D002220:Carbamazepine; D014635:Valproic Acid; D000077213:Lamotrigine