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. 2012 Dec;68(4):671-81. doi: 10.1007/s13105-012-0179-6. Epub 2012 Jun 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / metabolism*
  • Benzoxazines / pharmacology
  • Brain / metabolism*
  • Cannabinoid Receptor Agonists / pharmacology
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Endocannabinoids / physiology
  • Fatty Acids, Omega-3 / metabolism*
  • Female
  • MAP Kinase Signaling System*
  • Malnutrition / metabolism*
  • Malnutrition / psychology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Morpholines / pharmacology
  • Motor Activity
  • Naphthalenes / pharmacology
  • Receptors, Cannabinoid / metabolism*
  • Social Behavior


  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Endocannabinoids
  • Fatty Acids, Omega-3
  • Morpholines
  • Naphthalenes
  • Receptors, Cannabinoid
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3