Chronic Administration of Lamotrigine Downregulates COX-2 mRNA and Protein in Rat Frontal Cortex
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Chronic administration to rats of mood-stabilizers that are effective against mania in bipolar disorder, is reported to downregulate markers of the brain arachidonic acid cascade. We hypothesized that chronic administration of lamotrigine, which is used to treat depression and rapid cycling in bipolar disorder, might do so as well. Male CDF rats were administered a therapeutically relevant dose of lamotrigine (10 mg/kg) or vehicle intragastrically once daily for 42 days. Protein levels of isoforms of phospholipase A2 (PLA2) and of cyclooxygenase (COX), and the mRNA level of COX-2, were quantified in the frontal cortex using immunoblotting and RT-PCR, respectively. Compared to vehicle-treated rats, chronic lamotrigine significantly decreased frontal cortex protein and mRNA levels of COX-2 without altering protein levels of the PLA2 isoforms. Consistent with the hypothesis, lamotrigine and other mood-stabilizers have a common downregulatory action on COX-2 expression in rat brain, which may account in part for their efficacy in bipolar disorder.
KeywordsLamotrigine Brain Arachidonic acid cPLA2 COX-2 Bipolar disorder
Calcium-dependent cytosolich phospholipase A2
Calcium-independent phospholipase A2
Secretory phospholipase A2
We thank Dr. Bjornar Hassel for his valuable comments on the study design. This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
- 8.Murakami M, Shimbara S, Kambe T, Kuwata H, Winstead MV, Tischfield JA, Kudo I (1998) The functions of five distinct mammalian phospholipase A2S in regulating arachidonic acid release. Type IIa and type V secretory phospholipase A2S are functionally redundant and act in concert with cytosolic phospholipase A2. J Biol Chem 273:14411–14423PubMedCrossRefGoogle Scholar
- 9.Lands WEM, Crawford CG (1976) Enzymes of membrane phospholipid metabolism. Plenum, New York, pp 3–85Google Scholar
- 12.Bazinet RP, Rao JS, Chang L, Rapoport SI, Lee HJ (2006) Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder. Biol Psychiatry 59:401–407PubMedCrossRefGoogle Scholar
- 27.Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J (2003) A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 60:392–400PubMedCrossRefGoogle Scholar
- 36.Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME (2007) Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 356:1711–1722PubMedCrossRefGoogle Scholar
- 38.Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Moller HJ, Arolt V, Riedel M (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11:680–684PubMedCrossRefGoogle Scholar
- 39.Soares JC, Nery FG, Monkul ES, Fonseca M, Zunta GB, Frey BN, Hatch JP (2006) A COX-2 inhibitor (celecoxib) as a possible adjunctive agent to expedite treatment response in bipolar depression. ACNP Program No 71Google Scholar