title: Cannabinoid receptor activation prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of depression.
abstract: 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.
authors.affiliation: Department of Psychology, University of Haifa, Haifa, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Segev
authors.affiliation: Department of Psychology, University of Haifa, Haifa, Israel.
authors.forename: Adva S
authors.initials: AS
authors.lastname: Rubin
authors.affiliation: Department of Psychology, University of Haifa, Haifa, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Abush
authors.affiliation: 1] Department of Psychology, University of Haifa, Haifa, Israel [2] Department of Neurobiology, University of Haifa, Haifa, Israel [3] The Institute for the Study of Affective Neuroscience, University of Haifa, Haifa, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Richter-Levin
authors.affiliation: Department of Psychology, University of Haifa, Haifa, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Akirav
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005508:Food Deprivation; D005518:Food Preferences / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D009714:Nucleus Accumbens / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone