Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat
- 310 Downloads
Fluoxetine is used to treat unipolar depression and is thought to act by increasing the concentration of serotonin (5-HT) in the synaptic cleft, leading to increased serotonin signaling. The 5-HT2A/2C receptor subtypes are coupled to a phospholipase A2 (PLA2). We hypothesized that chronic fluoxetine would increase the brain activity of PLA2 and the turnover rate of arachidonic acid (AA) in phospholipids of the unanesthetized rat.
Materials and methods
To test this hypothesis, rats were administered fluoxetine (10 mg/kg) or vehicle intraperitoneally daily for 21 days. In the unanesthetized rat, [1-14C]AA was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min and its brain was subjected to chemical, radiotracer, or enzyme analysis.
Using equations from our fatty acid model, we found that chronic fluoxetine compared with vehicle increased the turnover rate of AA within several brain phospholipids by 75–86%. The activity and protein levels of brain cytosolic PLA2 (cPLA2) but not of secretory or calcium-independent PLA2 were increased in rats administered fluoxetine. In a separate group of animals that received chronic fluoxetine followed by a 3-day saline washout, the turnover of AA and activity and protein levels of cPLA2 were not significantly different from controls. The protein levels of cyclooxygenases 1 and 2 as well as the concentration of prostaglandin E2 in rats chronically administered fluoxetine did not differ significantly from controls.
The results support the hypothesis that fluoxetine increases the cPLA2-mediated turnover of AA within brain phospholipids.
KeywordsFluoxetine Brain Arachidonic acid Phospholipase A2 Cyclooxygenase Prostaglandin
This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
- Bazinet RP, Rao JS, Chang L, Rapoport SI, Lee HJ (2006a) 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 59:401–407CrossRefPubMedGoogle Scholar
- Bosetti F, Langenbach R, Weerasinghe GR (2004) Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+-dependent phospholipase A2. J Neurochem 91:1389–1397CrossRefPubMedGoogle Scholar
- Damjanoska KJ, Van de Kar LD, Kindel GH, Zhang Y, D’Souza DN, Garcia F, Battaglia G, Muma NA (2003) Chronic fluoxetine differentially affects 5-hydroxytryptamine (2A) receptor signaling in frontal cortex, oxytocin- and corticotropin-releasing factor-containing neurons in rat paraventricular nucleus. J Pharmacol Exp Ther 306:563–571CrossRefPubMedGoogle Scholar
- De Foubert G, Carney SL, Robinson CS, Destexhe EJ, Tomlinson R, Hicks CA, Murray TK, Gaillard JP, Deville C, Xhenseval V, Thomas CE, O’Neill MJ, Zetterstrom TS (2004) Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. Neuroscience 128:597–604CrossRefPubMedGoogle Scholar
- Felder CC, Kanterman RY, Ma AL, Axelrod J (1990) Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc Natl Acad Sci USA 87:2187–2191CrossRefPubMedPubMedCentralGoogle Scholar
- Hefner Y, Borsch-Haubold AG, Murakami M, Wilde JI, Pasquet S, Schieltz D, Ghomashchi F, Yates JR 3rd, Armstrong CG, Paterson A, Cohen P, Fukunaga R, Hunter T, Kudo I, Watson SP, Gelb MH (2000) Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases. J Biol Chem 275:37542–37551CrossRefPubMedGoogle Scholar
- Lands WEM, Crawford CG (1976) Enzymes of membrane phospholipid metabolism. In: Marinosi A (ed) The enzyme of biological membrane. pp 3–85Google Scholar
- Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE Jr, Kupka RW, Denicoff KD, Nolen WA, Grunze H, Martinez MI, Post RM (2006) Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry 163:232–239CrossRefPubMedGoogle Scholar
- Qu Y, Chang L, Klaff J, Seemann R, Greenstein D, Rapoport SI (2006) Chronic fluoxetine upregulates arachidonic acid incorporation into the brain of unanesthetized rats. Eur Neuropsychopharmacol (in press)Google Scholar
- 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 (in press). DOI 10.1038/sj.tpj.6500391
- Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A (2003) Efficacy of olanzapine and olanzapine–fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60:1079–1088CrossRefPubMedGoogle Scholar