Cannabinoid receptor type 1 modulates the effects of polyunsaturated fatty acids on memory of stressed rats

Nutr Neurosci. 2021 Aug;24(8):583-600. doi: 10.1080/1028415X.2019.1659561. Epub 2019 Oct 22.


Memory and GABAergic activity in the hippocampus of stressed rats improve after n-3 polyunsaturated fatty acid (PUFA) supplementation. On the other hand, cannabinoid receptor type 1 (CB1) strongly regulates inhibitory neurotransmission in the hippocampus. Speculation about a possible relation between stress, endocannabinoids, and PUFAs. Here, we examined whether the effects of PUFAs on memory of chronically stressed rats depends on pharmacological manipulation of CB1 receptors. Male Sprague-Dawley rats were orally supplemented with n-3 (fish oil) or n-6 (primrose oil) PUFAs during chronic restraint stress (CRS) protocol (6 h/day; 21 days). First, we studied if the expression of CB1 receptors in the hippocampus may be affected by CRS and PUFAs supplementation by real-time PCR and immunofluorescence. CRS up-regulated the CB1 expression compared with the non-stressed rats, while only n-3 PUFAs countered this effect. Memory was evaluated in the Morris water maze. Stressed rats were co-treated with PUFAs and/or modulators of CB1 receptor (AM251, antagonist, 0.3 mg/kg/day; WIN55,212-2, agonist, 0.5 mg/kg/day) by intraperitoneal injections. Memory improved in the stressed rats that were treated with AM251 and/or n-3 PUFAs. Supplementation with n-6 PUFAs did not affect memory of stressed rats, but co-treatment with AM251 improved it, while co-treatment with WIN55,212-2 did not affect memory. Our results demonstrate that activity of the CB1 receptors may modulate the effects of PUFAs on memory of stressed rats. This study suggests that endocannabinoids and PUFAs can both become a singular system by being self-regulated in limbic areas, so they control the effects of stress on the brain.

Keywords: PUFA; Stress; endocannabinoids; hippocampus; memory consolidation.

MeSH terms

  • Animals
  • Fatty Acids, Unsaturated / administration & dosage*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism*
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects*
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Stress, Psychological / physiopathology*
  • Stress, Psychological / psychology*


  • Cnr1 protein, rat
  • Fatty Acids, Unsaturated
  • Receptor, Cannabinoid, CB1