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Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression

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Abstract

Brain serotonergic signaling is coupled to arachidonic acid (AA)-releasing calcium-dependent phospholipase A2. Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders Sensitive Line (FSL) rat model of depression, suggesting that brain AA metabolism may be elevated. To test this hypothesis, 14C-AA was intravenously infused to steady-state levels into control and FSL rats derived from the same Sprague–Dawley background strain, and labeled and unlabeled brain phospholipid and plasma fatty acid concentrations were measured to determine the rate of brain AA incorporation and turnover. Brain AA incorporation and turnover did not differ significantly between controls and FSL rats. Compared to controls, plasma unesterified docosahexaenoic acid was increased, and brain phosphatidylinositol AA and total lipid linoleic acid and n-3 and n-6 docosapentaenoic acid were significantly decreased in FSL rats. Several plasma esterified fatty acids differed significantly from controls. In summary, brain AA metabolism did not change in FSL rats despite reported increased levels of serotonin concentrations, suggesting possible post-synaptic dampening of serotonergic neurotransmission involving AA.

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Abbreviations

5-HT:

Serotonin

5-HTT:

5-HT transporter

α-LNA:

Alpha-linolenic acid

AA:

Arachidonic acid

AA-CoA:

Arachidonoyl-CoA

AUC:

Area under the curve

ChoGpl:

Choline glycerophospholipid

cPLA2 :

Cytosolic phospholipase A2

CSF:

Cerebrospinal fluid

DFP:

Diisopropyl fluorophosphate

DHA:

Docosahexaenoic acid

DOI:

2,5-Dimethoxy-4-iodoamphetamine hydrochloride

GC :

Gas Chromatography

EtnGpl:

Ethanolamine glycerophospholipid

DPA:

Docosapentaenoic acid

EPA:

Eicosapentaenoic acid

FAME:

Fatty Acid Methyl Ester

FRL:

Flinders Resistant Line

FSL:

Flinders Sensitive Line

LA:

Linoleic acid

PtdIns:

Phosphatidylinositol

PdtSer:

Phosphatidylserine

SFA:

Saturated fatty acids

MUFA:

Monounsaturated fatty acids

PUFA:

Polyunsaturated fatty acids

SD:

Sprague–Dawley

SSRI:

Selective serotonin reuptake inhibitors

TLC:

Thin Layer Chromatography

References

  1. Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295

    CAS  PubMed  Google Scholar 

  2. Cheetham SC, Crompton MR, Katona CL, Horton RW (1988) Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res 443:272–280

    Article  CAS  PubMed  Google Scholar 

  3. Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ (2004) Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography. Biol Psychiatry 55:217–224

    Article  CAS  PubMed  Google Scholar 

  4. Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57:174–180

    Article  CAS  PubMed  Google Scholar 

  5. Meyer JH, Houle S, Sagrati S, Carella A, Hussey DF, Ginovart N, Goulding V, Kennedy J, Wilson AA (2004) Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61:1271–1279

    Article  CAS  PubMed  Google Scholar 

  6. Meyer JH, Wilson AA, Sagrati S, Miler L, Rusjan P, Bloomfield PM, Clark M, Sacher J, Voineskos AN, Houle S (2009) Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence. Arch Gen Psychiatry 66:1304–1312

    Article  PubMed  Google Scholar 

  7. Kovacevic T, Skelin I, Diksic M (2010) Chronic fluoxetine treatment has a larger effect on the density of a serotonin transporter in the Flinders Sensitive Line (FSL) rat model of depression than in normal rats. Synapse 64:231–240

    Article  CAS  PubMed  Google Scholar 

  8. Garcia MC, Kim HY (1997) Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6 glioma cells. Brain Res 768:43–48

    Article  CAS  PubMed  Google Scholar 

  9. Strokin M, Sergeeva M, Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br J Pharmacol 139:1014–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Qu Y, Chang L, Klaff J, Balbo A, Rapoport SI (2003) Imaging brain phospholipase A2 activation in awake rats in response to the 5-HT2A/2C agonist (±)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI). Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 28:244–252

    Article  CAS  Google Scholar 

  11. Qu Y, Chang L, Klaff J, Seemann R, Rapoport SI (2003) Imaging brain phospholipase A2-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 28:1219–1226

    Article  CAS  Google Scholar 

  12. 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 J Eur Coll Neuropsychopharmacol 16:561–571

    Article  CAS  Google Scholar 

  13. 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 190:103–115

    Article  CAS  PubMed  Google Scholar 

  14. Axelrod J (1990) Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem Soc Trans 18:503–507

    Article  CAS  PubMed  Google Scholar 

  15. 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 87:2187–2191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Overstreet DH, Friedman E, Mathe AA, Yadid G (2005) The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 29:739–759

    Article  CAS  PubMed  Google Scholar 

  17. Overstreet DH (1993) The Flinders Sensitive Line rats: a genetic animal model of depression. Neurosci Biobehav Rev 17:51–68

    Article  CAS  PubMed  Google Scholar 

  18. Yadid G, Nakash R, Deri I, Tamar G, Kinor N, Gispan I, Zangen A (2000) Elucidation of the neurobiology of depression: insights from a novel genetic animal model. Prog Neurobiol 62:353–378

    Article  CAS  PubMed  Google Scholar 

  19. Hasegawa S, Nishi K, Watanabe A, Overstreet DH, Diksic M (2006) Brain 5-HT synthesis in the Flinders Sensitive Line rat model of depression: an autoradiographic study. Neurochem Int 48:358–366

    Article  CAS  PubMed  Google Scholar 

  20. Zangen A, Overstreet DH, Yadid G (1997) High serotonin and 5-hydroxyindoleacetic acid levels in limbic brain regions in a rat model of depression: normalization by chronic antidepressant treatment. J Neurochem 69:2477–2483

    Article  CAS  PubMed  Google Scholar 

  21. Nishi K, Kanemaru K, Diksic M (2009) A genetic rat model of depression, Flinders Sensitive Line, has a lower density of 5-HT(1A) receptors, but a higher density of 5-HT(1B) receptors, compared to control rats. Neurochem Int 54:299–307

    Article  CAS  PubMed  Google Scholar 

  22. Iritani S, Tohgi M, Arai T, Ikeda K (2006) Immunohistochemical study of the serotonergic neuronal system in an animal model of the mood disorder. Exp Neurol 201:60–65

    Article  CAS  PubMed  Google Scholar 

  23. Osterlund MK, Overstreet DH, Hurd YL (1999) The Flinders Sensitive Line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17beta-estradiol. Brain Res Mol Brain Res 74:158–166

    Article  CAS  PubMed  Google Scholar 

  24. Benca RM, Overstreet DE, Gilliland MA, Russell D, Bergmann BM, Obermeyer WH (1996) Increased basal REM sleep but no difference in dark induction or light suppression of REM sleep in flinders rats with cholinergic supersensitivity. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 15:45–51

    Article  CAS  Google Scholar 

  25. Zangen A, Overstreet DH, Yadid G (1999) Increased catecholamine levels in specific brain regions of a rat model of depression: normalization by chronic antidepressant treatment. Brain Res 824:243–250

    Article  CAS  PubMed  Google Scholar 

  26. Dremencov E, Newman ME, Kinor N, Blatman-Jan G, Schindler CJ, Overstreet DH, Yadid G (2005) Hyperfunctionality of serotonin-2C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment. Neuropharmacology 48:34–42

    Article  CAS  PubMed  Google Scholar 

  27. Gomez-Galan M, De Bundel D, Van Eeckhaut A, Smolders I, Lindskog M (2013) Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression. Mol Psychiatry 18:582–594

    Article  CAS  PubMed  Google Scholar 

  28. Green P, Anyakoha N, Yadid G, Gispan-Herman I, Nicolaou A (2009) Arachidonic acid-containing phosphatidylcholine species are increased in selected brain regions of a depressive animal model: implications for pathophysiology. Prostaglandins Leukot Essent Fatty Acids 80:213–220

    Article  CAS  PubMed  Google Scholar 

  29. Green P, Gispan-Herman I, Yadid G (2005) Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression. J Lipid Res 46:1093–1096

    Article  CAS  PubMed  Google Scholar 

  30. Robinson PJ, Noronha J, DeGeorge JJ, Freed LM, Nariai T, Rapoport SI (1992) A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis. Brain Res Brain Res Rev 17:187–214

    Article  CAS  PubMed  Google Scholar 

  31. DeGeorge JJ, Noronha JG, Bell J, Robinson P, Rapoport SI (1989) Intravenous injection of [1-14C]arachidonate to examine regional brain lipid metabolism in unanesthetized rats. J Neurosci Res 24:413–423

    Article  CAS  PubMed  Google Scholar 

  32. Overstreet DH, Russell RW, Helps SC, Messenger M (1979) Selective breeding for sensitivity to the anticholinesterase DFP. Psychopharmacology 65:15–20

    Article  CAS  PubMed  Google Scholar 

  33. Igarashi M, Gao F, Kim HW, Ma K, Bell JM, Rapoport SI (2009) Dietary n-6 PUFA deprivation for 15 weeks reduces arachidonic acid concentrations while increasing n-3 PUFA concentrations in organs of post-weaning male rats. Biochim Biophys Acta 1791:132–139

    Article  CAS  PubMed  Google Scholar 

  34. Modi HR, Taha AY, Kim HW, Chang L, Rapoport SI, Cheon Y (2013) Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability. J Neurochem 124:376–387

    Article  CAS  PubMed  Google Scholar 

  35. Washizaki K, Smith QR, Rapoport SI, Purdon AD (1994) Brain arachidonic acid incorporation and precursor pool specific activity during intravenous infusion of unesterified [3H]arachidonate in the anesthetized rat. J Neurochem 63:727–736

    Article  CAS  PubMed  Google Scholar 

  36. Deutsch J, Rapoport SI, Purdon AD (1997) Relation between free fatty acid and acyl-CoA concentrations in rat brain following decapitation. Neurochem Res 22:759–765

    Article  CAS  PubMed  Google Scholar 

  37. Bazinet RP, Lee HJ, Felder CC, Porter AC, Rapoport SI, Rosenberger TA (2005) Rapid high-energy microwave fixation is required to determine the anandamide (N-arachidonoylethanolamine) concentration of rat brain. Neurochem Res 30:597–601

    Article  CAS  PubMed  Google Scholar 

  38. Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509

    CAS  PubMed  Google Scholar 

  39. Skipski VP, Good JJ, Barclay M, Reggio RB (1968) Quantitative analysis of simple lipid classes by thin-layer chromatography. Biochim Biophys Acta 152:10–19

    Article  CAS  PubMed  Google Scholar 

  40. Skipski VP, Barclay M, Reichman ES, Good JJ (1967) Separation of acidic phospholipids by one-dimensional thin-layer chromatography. Biochim Biophys Acta 137:80–89

    Article  CAS  PubMed  Google Scholar 

  41. Deutsch J, Grange E, Rapoport SI, Purdon AD (1994) Isolation and quantitation of long-chain acyl-coenzyme A esters in brain tissue by solid-phase extraction. Anal Biochem 220:321–323

    Article  CAS  PubMed  Google Scholar 

  42. Rapoport SI, Chang MC, Spector AA (2001) Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. J Lipid Res 42:678–685

    CAS  PubMed  Google Scholar 

  43. DeMar JC Jr, Lee HJ, Ma K, Chang L, Bell JM, Rapoport SI, Bazinet RP (2006) Brain elongation of linoleic acid is a negligible source of the arachidonate in brain phospholipids of adult rats. Biochim Biophys Acta 1761:1050–1059

    Article  CAS  PubMed  Google Scholar 

  44. Berry SA, Shah MC, Khan N, Roth BL (1996) Rapid agonist-induced internalization of the 5-hydroxytryptamine2A receptor occurs via the endosome pathway in vitro. Mol Pharmacol 50:306–313

    CAS  PubMed  Google Scholar 

  45. Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, Herrick-Davis K (2000) Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors. Synapse 35:144–150

    Article  CAS  PubMed  Google Scholar 

  46. Bhattacharjee AK, Chang L, White L, Bazinet RP, Rapoport SI (2008) Imaging apomorphine stimulation of brain arachidonic acid signaling via D2-like receptors in unanesthetized rats. Psychopharmacology 197:557–566

    Article  CAS  PubMed  Google Scholar 

  47. Vial D, Piomelli D (1995) Dopamine D2 receptors potentiate arachidonate release via activation of cytosolic, arachidonate-specific phospholipase A2. J Neurochem 64:2765–2772

    Article  CAS  PubMed  Google Scholar 

  48. Ramadan E, Chang L, Chen M, Ma K, Hall FS, Uhl GR, Rapoport SI, Basselin M (2012) Knocking out the dopamine reuptake transporter (DAT) does not change the baseline brain arachidonic acid signal in the mouse. Int J Neurosci 122:373–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. http://www.harlan.com/products_and_services/research_models_and_services/tekladdiets/teklad_natural_ingredient_diets/teklad_global_diets/global_rodent_diets/Teklad_global_18_rodent_diet_sterilizable_2018s.hl

  50. Qu Y, Villacreses N, Murphy DL, Rapoport SI (2005) 5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter. Psychopharmacology 180:12–20

    Article  CAS  PubMed  Google Scholar 

  51. Esposito G, Giovacchini G, Liow JS, Bhattacharjee AK, Greenstein D, Schapiro M, Hallett M, Herscovitch P, Eckelman WC, Carson RE, Rapoport SI (2008) Imaging neuroinflammation in Alzheimer’s disease with radiolabeled arachidonic acid and PET. J Nucl Med Off Publ Soc Nucl Med 49:1414–1421

    CAS  Google Scholar 

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Acknowledgments

We thank Dr. Epolia Ramadan and Dr. Mireille Basselin for writing the animal study protocol and Dr. Mei Chen for technical assistance.

Source of Funding

Research was supported by the Intramural Research Program of the National Institute on Aging.

Author information

Authors and Affiliations

  1. Brain Physiology and Metabolism Section, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    Helene Blanchard, Lisa Chang & Stanley I. Rapoport

  2. Department of Psychiatric and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    Amir H. Rezvani

  3. Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, RMI North, Room 3162, Davis, CA, USA

    Ameer Y. Taha

Authors
  1. Helene Blanchard
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  2. Lisa Chang
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  3. Amir H. Rezvani
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  4. Stanley I. Rapoport
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  5. Ameer Y. Taha
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Correspondence to Ameer Y. Taha.

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Blanchard, H., Chang, L., Rezvani, A.H. et al. Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression. Neurochem Res 40, 2293–2303 (2015). https://doi.org/10.1007/s11064-015-1719-6

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  • DOI: https://doi.org/10.1007/s11064-015-1719-6

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