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

Amir Segev, Adva S. Rubin, Hila Abush, Gal Richter-Levin, Irit Akirav

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)919-933
Number of pages15
JournalNeuropsychopharmacology
Volume39
Issue number4
DOIs
StatePublished - Mar 2014

Bibliographical note

Funding Information:
This research was supported by THE ISRAEL SCIENCE FOUNDATION grant No. 222/08 to IA and by a grant from the Hope for Depression Research Foundation to GR-L.

Keywords

  • 212-2
  • LTP
  • WIN55
  • depression
  • extinction
  • glucocorticoid receptors
  • nucleus accumbens

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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