Cannabinoid receptor activation prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of depression

Neuropsychopharmacology. 2014 Mar;39(4):919-33. doi: 10.1038/npp.2013.292. Epub 2013 Oct 21.


Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1-21. The agonist WIN55,212-2 or vehicle were administered on days 19-21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning / drug effects
  • Benzoxazines / pharmacology
  • Benzoxazines / therapeutic use
  • Body Weight / drug effects
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Agonists / therapeutic use
  • Cannabinoid Receptor Antagonists / pharmacology
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Food Deprivation
  • Food Preferences / drug effects
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Male
  • Morpholines / pharmacology
  • Morpholines / therapeutic use
  • Naphthalenes / pharmacology
  • Naphthalenes / therapeutic use
  • Nucleus Accumbens / drug effects
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cannabinoid / metabolism*
  • Stress, Psychological / metabolism*
  • Stress, Psychological / prevention & control*


  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptors, Cannabinoid
  • AM 251
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone