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Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice

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Abstract

N-3 polyunsaturated fatty acids (PUFAs) cannot be synthesized de novo in mammals and need to be provided by dietary means. In the brain, the main n-3 PUFA is docosahexaenoic acid (DHA), which is a key component of neuronal membranes. A low dietary level of DHA has been associated with increased risk of developing neuropsychiatric diseases; however, the mechanisms involved remain to be determined. In this study, we found that long-term exposure to an n-3 deficient diet decreases the level of DHA in the brain and impairs the cannabinoid receptor signaling pathway in mood-controlling structures. In n-3 deficient mice, the effect of the cannabinoid agonist WIN55,212-2 in an anxiety-like behavior test was abolished. In addition, the cannabinoid receptor signaling pathways were altered in the prefrontal cortex and the hypothalamus. Consequently, our data suggest that behavioral changes linked to an n-3 dietary deficiency are due to an alteration in the endocannabinoid system in specific brain areas.

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References

  1. Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 10(4):345–352

    Article  PubMed  CAS  Google Scholar 

  2. Bouaboula M, Bourrie B, Rinaldi-Carmona M, Shire D, Le Fur G, Casellas P (1995) Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J Biol Chem 270(23):13973–13980

    Article  PubMed  CAS  Google Scholar 

  3. Bouaboula M, Poinot-Chazel C, Bourrie B, Canat X, Calandra B, Rinaldi-Carmona M, Le Fur G, Casellas P (1995) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 312(Pt 2):637–641

    PubMed  CAS  Google Scholar 

  4. Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, Kim HY (2009) Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J Neurochem 111(2):510–521

    Article  PubMed  CAS  Google Scholar 

  5. Carrie I, Clement M, de Javel D, Frances H, Bourre JM (2000) Specific phospholipid fatty acid composition of brain regions in mice. Effects of n-3 polyunsaturated fatty acid deficiency and phospholipid supplementation. J Lipid Res 41(3):465–472

    PubMed  CAS  Google Scholar 

  6. Chalon S (2006) Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent Fatty Acids 75(4–5):259–269

    Article  PubMed  CAS  Google Scholar 

  7. Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, LaPlant Q, Mouzon E, Ghose S, Tamminga CA, Neve RL, Deisseroth K, Nestler EJ (2010) Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci 30(48):16082–16090

    Article  PubMed  CAS  Google Scholar 

  8. DeMar JC Jr, Ma K, Bell JM, Igarashi M, Greenstein D, Rapoport SI (2006) One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J Lipid Res 47(1):172–180

    Article  PubMed  CAS  Google Scholar 

  9. Derkinderen P, Valjent E, Toutant M, Corvol JC, Enslen H, Ledent C, Trzaskos J, Caboche J, Girault JA (2003) Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J Neurosci 23(6):2371–2382

    PubMed  CAS  Google Scholar 

  10. Fedorova I, Hussein N, Di Martino C, Moriguchi T, Hoshiba J, Majchrzak S, Salem N Jr (2007) An n-3 fatty acid deficient diet affects mouse spatial learning in the Barnes circular maze. Prostaglandins Leukot Essent Fatty Acids 77(5–6):269–277

    Article  PubMed  CAS  Google Scholar 

  11. Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226(1):497–509

    PubMed  CAS  Google Scholar 

  12. Hibbeln JR (1998) Fish consumption and major depression. Lancet 351(9110):1213

    Article  PubMed  CAS  Google Scholar 

  13. Hill MN, Gorzalka BB (2009) The endocannabinoid system and the treatment of mood and anxiety disorders. CNS Neurol Disord Drug Targets 8(6):451–458

    Article  PubMed  CAS  Google Scholar 

  14. Hill MN, Hillard CJ, McEwen BS (2011) Alterations in corticolimbic dendritic morphology and emotional behavior in cannabinoid CB1 receptor-deficient mice parallel the effects of chronic stress. Cereb Cortex 21(9):2056–2064

    Article  PubMed  Google Scholar 

  15. Kitajka K, Sinclair AJ, Weisinger RS, Weisinger HS, Mathai M, Jayasooriya AP, Halver JE, Puskas LG (2004) Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc Natl Acad Sci U S A 101(30):10931–10936

    Article  PubMed  CAS  Google Scholar 

  16. Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodriguez-Puertas R, Laye S, Manzoni OJ (2011) Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci 14(3):345–350

    Article  PubMed  CAS  Google Scholar 

  17. Levant B, Ozias MK, Carlson SE (2007) Specific brain regions of female rats are differentially depleted of docosahexaenoic acid by reproductive activity and an (n-3) fatty acid-deficient diet. J Nutr 137(1):130–134

    PubMed  CAS  Google Scholar 

  18. Lutz B (2009) Endocannabinoid signals in the control of emotion. Curr Opin Pharmacol 9(1):46–52

    Article  PubMed  CAS  Google Scholar 

  19. McNamara RK (2010) DHA deficiency and prefrontal cortex neuropathology in recurrent affective disorders. J Nutr 140(4):864–868

    Article  PubMed  CAS  Google Scholar 

  20. Mingam R, Moranis A, Bluthe RM, De Smedt-Peyrusse V, Kelley KW, Guesnet P, Lavialle M, Dantzer R, Laye S (2008) Uncoupling of interleukin-6 from its signalling pathway by dietary n-3-polyunsaturated fatty acid deprivation alters sickness behaviour in mice. Eur J Neurosci 28(9):1877–1886

    Article  PubMed  Google Scholar 

  21. Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S, Parada LF, Nestler EJ (2007) Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry 61(2):187–197

    Article  PubMed  CAS  Google Scholar 

  22. Moranis A, Delpech JC, De Smedt-Peyrusse V, Aubert A, Guesnet P, Lavialle M, Joffre C, Laye S (2011) Long term adequate n-3 polyunsaturated fatty acid diet protects from depressive-like behavior but not from working memory disruption and brain cytokine expression in aged mice. Brain Behav Immun

  23. Moriguchi T, Greiner RS, Salem N Jr (2000) Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration. J Neurochem 75(6):2563–2573

    Article  PubMed  CAS  Google Scholar 

  24. Morrison WR, Smith LM (1964) Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride–methanol. J Lipid Res 5:600–608

    PubMed  CAS  Google Scholar 

  25. Rao JS, Ertley RN, Lee HJ, DeMar JC Jr, Arnold JT, Rapoport SI, Bazinet RP (2007) n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol Psychiatry 12(1):36–46

    Article  PubMed  CAS  Google Scholar 

  26. Rodgers RJ, Evans PM, Murphy A (2005) Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naive and plus-maze-experienced mice. Behav Pharmacol 16(5–6):405–413

    Article  PubMed  CAS  Google Scholar 

  27. Salem N Jr, Litman B, Kim HY, Gawrisch K (2001) Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36(9):945–959

    Article  PubMed  CAS  Google Scholar 

  28. Shepherd JD, Bear MF (2011) New views of Arc, a master regulator of synaptic plasticity. Nat Neurosci 14(3):279–284

    Article  PubMed  CAS  Google Scholar 

  29. Simopoulos AP (2000) Human requirement for N-3 polyunsaturated fatty acids. Poult Sci 79(7):961–970

    PubMed  CAS  Google Scholar 

  30. Sinclair AJ (1975) Incorporation of radioactive polyunsaturated fatty acids into liver and brain of developing rat. Lipids 10(3):175–184

    Article  PubMed  CAS  Google Scholar 

  31. Steiner MA, Wanisch K, Monory K, Marsicano G, Borroni E, Bachli H, Holsboer F, Lutz B, Wotjak CT (2008) Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice. Pharmacogenomics J 8(3):196–208

    Article  PubMed  CAS  Google Scholar 

  32. Wartmann M, Campbell D, Subramanian A, Burstein SH, Davis RJ (1995) The MAP kinase signal transduction pathway is activated by the endogenous cannabinoid anandamide. FEBS Lett 359(2–3):133–136

    Article  PubMed  CAS  Google Scholar 

  33. Watanabe S, Doshi M, Hamazaki T (2003) n-3 Polyunsaturated fatty acid (PUFA) deficiency elevates and n-3 PUFA enrichment reduces brain 2-arachidonoylglycerol level in mice. Prostaglandins Leukot Essent Fatty Acids 69(1):51–59

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was financially supported by INRA, FRM, and the Région Aquitaine. T.L. received stipend from ANR and CM from the Ministry of French Research. The authors thank P. Birac, C. Tridon, and M. Cadet for taking care of the mice and V. DeSmedt and C. Vaysse (ITERG, Pessac, France) for helpful support.

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Correspondence to Sophie Layé.

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Thomas Larrieu and Charlotte Madore equally contributed to this work.

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Larrieu, T., Madore, C., Joffre, C. et al. Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice. J Physiol Biochem 68, 671–681 (2012). https://doi.org/10.1007/s13105-012-0179-6

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  • DOI: https://doi.org/10.1007/s13105-012-0179-6

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