Abstract
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.
Similar content being viewed by others
Abbreviations
- COX:
-
Cyclooxygenase
- cPLA2 :
-
Calcium-dependent cytosolich phospholipase A2
- iPLA2 :
-
Calcium-independent phospholipase A2
- sPLA2 :
-
Secretory phospholipase A2
- Sn :
-
Stereospecifically numbered
References
Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD (1999) A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 60:79–88
Calabrese JR, Rapport DJ, Youngstrom EA, Jackson K, Bilali S, Findling RL (2005) New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder. Eur Psychiatry 20:92–95
Hassel B, Tauboll E, Gjerstad L (2001) Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels. Epilepsy Res 43:153–163
Ahmad S, Fowler LJ, Whitton PS (2004) Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat. Br J Pharmacol 142:136–142
Ahmad S, Fowler LJ, Whitton PS (2005) Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats. Naunyn-Schmiedeberg’s Arch Pharmacol 371:1–8
Channon JY, Leslie CC (1990) A calcium-dependent mechanism for associating a soluble arachidonoyl-hydrolyzing phospholipase A2 with membrane in the macrophage cell line RAW 264.7. J Biol Chem 265:5409–5413
Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P (1996) COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 93:2317–2321
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 273:14411–14423
Lands WEM, Crawford CG (1976) Enzymes of membrane phospholipid metabolism. Plenum, New York, pp 3–85
Leslie JB, Watkins WD (1985) Eicosanoids in the central nervous system. J Neurosurg 63:659–668
O’Banion MK (1999) Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology. Crit Rev Neurobiol 13:45–82
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 59:401–407
Chang MC, Contreras MA, Rosenberger TA, Rintala JJ, Bell JM, Rapoport SI (2001) Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers. J Neurochem 77:796–803
Chang MC, Grange E, Rabin O, Bell JM, Allen DD, Rapoport SI (1996) Lithium decreases turnover of arachidonate in several brain phospholipids. Neurosci Lett 220:171–174
Ghelardoni S, Tomita YA, Bell JM, Rapoport SI, Bosetti F (2004) Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain. Biol Psychiatry 56:248–254
Rao JS, Bazinet RP, Rapoport SI, Lee HJ (2007) Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-kappaB DNA binding activity and COX-2 mRNA. Bipolar Disord 9:513–520
Rintala J, Seemann R, Chandrasekaran K, Rosenberger TA, Chang L, Contreras MA, Contreras MA, Rapoport SI, Chang MC (1999) 85 kDa cytosolic phospholipase A2 is a target for chronic lithium in rat brain. Neuroreport 10:3887–3890
Rao JS, Bazinet RP, Rapoport SI, Lee HJ (2007) Chronic administration of carbamazepine down-regulates AP-2 DNA-binding activity and AP-2alpha protein expression in rat frontal cortex. Biol Psychiatry 61:154–161
Rao JS, Rapoport SI, Bosetti F (2005) Decrease in the AP-2 DNA-binding activity and in the protein expression of AP-2 alpha and AP-2 beta in frontal cortex of rats treated with lithium for 6 weeks. Neuropsychopharmacology 30:2006–2013
Bosetti F, Rintala J, Seemann R, Rosenberger TA, Contreras MA, Rapoport SI, Chang MC (2002) Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain. Mol Psychiatry 7:845–850
Bosetti F, Weerasinghe GR, Rosenberger TA, Rapoport SI (2003) Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and -2 in rat brain. J Neurochem 85:690–696
McElroy SL, Suppes T, Keck PE, Frye MA, Denicoff KD, Altshuler LL, Brown ES, Nolen WA, Kupka RW, Rochussen J, Leverich GS, Post RM (2000) Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry 47:1025–1033
Kushner SF, Khan A, Lane R, Olson WH (2006) Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord 8:15–27
Ghelardoni S, Bazinet RP, Rapoport SI, Bosetti F (2005) Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism. Psychopharmacology (Berl) 180:523–529
Lee HJ, Ghelardoni S, Chang L, Bosetti F, Rapoport SI, Bazinet RP (2005) Topiramate does not alter the kinetics of arachidonic or docosahexaenoic acid in brain phospholipids of the unanesthetized rat. Neurochem Res 30:677–683
Feder R (1990) Fluoxetine-induced mania. J Clin Psychiatry 51:524–525
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 60:392–400
Fatemi SH, Rapport DJ, Calabrese JR, Thuras P (1997) Lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 58:522–527
Lee HJ, Rao JS, Chang L, Rapoport SI, Bazinet RP (2007) Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder. Psychopharmacology (Berl) 193:467–474
Lyoo IK, Kim MJ, Stoll AL, Demopulos CM, Parow AM, Dager SR, Friedman SD, Dunner DL, Renshaw PF (2004) Frontal lobe gray matter density decreases in bipolar I disorder. Biol Psychiatry 55:648–651
Rajkowska G (2002) Cell pathology in bipolar disorder. Bipolar Disord 4:105–116
Doose DR, Brodie MJ, Wilson EA, Chadwick D, Oxbury J, Berry DJ, Schwabe S, Bialer M (2003) Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients. Epilepsia 44:917–922
Rao JS, Ertley RN, Lee HJ, Rapoport SI, Bazinet RP (2006) Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex. Pharmacogenomics J 6:413–420
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408
Rapoport SI, Bosetti F (2002) Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch Gen Psychiatry 59:592–596
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 356:1711–1722
Lee HJ, Rao JS, Ertley RN, Chang L, Rapoport SI, Bazinet RP (2007) Chronic fluoxetine increases cytosolic phospholipase A(2) activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat. Psychopharmacology (Berl) 190:103–115
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 11:680–684
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 71
Dembo G, Park SB, Kharasch ED (2005) Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans. Anesthesiology 102:409–415
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lee, HJ., Ertley, R.N., Rapoport, S.I. et al. Chronic Administration of Lamotrigine Downregulates COX-2 mRNA and Protein in Rat Frontal Cortex. Neurochem Res 33, 861–866 (2008). https://doi.org/10.1007/s11064-007-9526-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-007-9526-3