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.
Similar content being viewed by others
References
Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 10(4):345–352
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
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
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
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
Chalon S (2006) Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent Fatty Acids 75(4–5):259–269
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
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
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
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
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
Hibbeln JR (1998) Fish consumption and major depression. Lancet 351(9110):1213
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
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
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
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
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
Lutz B (2009) Endocannabinoid signals in the control of emotion. Curr Opin Pharmacol 9(1):46–52
McNamara RK (2010) DHA deficiency and prefrontal cortex neuropathology in recurrent affective disorders. J Nutr 140(4):864–868
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
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
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
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
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
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
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
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
Shepherd JD, Bear MF (2011) New views of Arc, a master regulator of synaptic plasticity. Nat Neurosci 14(3):279–284
Simopoulos AP (2000) Human requirement for N-3 polyunsaturated fatty acids. Poult Sci 79(7):961–970
Sinclair AJ (1975) Incorporation of radioactive polyunsaturated fatty acids into liver and brain of developing rat. Lipids 10(3):175–184
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
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
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
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Thomas Larrieu and Charlotte Madore equally contributed to this work.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13105-012-0179-6