Anandamide reverses depressive-like behavior, neurochemical abnormalities and oxidative-stress parameters in streptozotocin-diabetic rats: Role of CB1 receptors

Eur Neuropsychopharmacol. 2016 Oct;26(10):1590-600. doi: 10.1016/j.euroneuro.2016.08.007. Epub 2016 Aug 17.


The pathophysiology associated with increased prevalence of depression in diabetics is not completely understood, although studies have pointed the endocannabinoid system as a possible target. Then, we aimed to investigate the role of this system in the pathophysiology of depression associated with diabetes. For this, diabetic (DBT) male Wistar rats were intraperitoneally treated with cannabinoid CB1 (AM251, 1mg/kg) or CB2 (AM630, 1mg/kg) receptor antagonists followed by anandamide (AEA, 0.005mg/kg) and then submitted to the forced swimming test (FST). Oxidative stress parameters, CB1 receptor expression and serotonin (5-HT) and noradrenaline levels in the hippocampus (HIP) and prefrontal cortex (PFC) were also performed. It was observed that DBT animals presented a more pronounced depressive-like behavior and increase of CB1 receptor expression in the HIP. AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain. AEA was also able to restore the elevated CB1 expression and also to elevate the reduced level of 5-HT in the HIP from DBT animals. In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC. Together, our data suggest that in depression associated with diabetes, the endocannabinoid anandamide has a potential to induce neuroadaptative changes able to improve the depressive-like response by its action as a CB1 receptor agonist.

Keywords: CB1 receptor; Depression; Diabetes; Noradrenaline; Oxidative stress; Serotonin.

MeSH terms

  • Animals
  • Arachidonic Acids / therapeutic use*
  • Behavior, Animal / drug effects*
  • Brain Chemistry / drug effects*
  • Calcium Channel Blockers / therapeutic use*
  • Depression / drug therapy*
  • Depression / etiology*
  • Diabetes Mellitus, Experimental / psychology*
  • Endocannabinoids / therapeutic use*
  • Indoles / pharmacology
  • Male
  • Norepinephrine / metabolism
  • Oxidative Stress / drug effects*
  • Piperidines / pharmacology
  • Polyunsaturated Alkamides / therapeutic use*
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / biosynthesis
  • Receptor, Cannabinoid, CB1 / drug effects*
  • Serotonin / metabolism
  • Swimming / psychology


  • Arachidonic Acids
  • Calcium Channel Blockers
  • Endocannabinoids
  • Indoles
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Serotonin
  • AM 251
  • iodopravadoline
  • anandamide
  • Norepinephrine