Deficiency in endocannabinoid signaling in the nucleus accumbens induced by chronic unpredictable stress

Neuropsychopharmacology. 2010 Oct;35(11):2249-61. doi: 10.1038/npp.2010.99. Epub 2010 Jul 21.


The nucleus accumbens (NAc) is a critical component of the reward circuitry, and dysfunction of the NAc may account for anhedonia and other symptoms of depression. Here, we investigated whether alterations in endocannabinoid (eCB) signaling in the NAc contribute to depression-like behaviors induced by chronic unpredictable stress (CUS) in mice. We compared three types of eCB/CB1 receptor-mediated synaptic plasticity in slices prepared from the NAc core of control and stress-exposed mice: depolarization-induced suppression of excitation, long-term depression, and the depression of field excitatory postsynaptic potentials (fEPSPs) induced by group I metabotropic glutamate receptor agonist DHPG. CUS (5-6-week exposure to stressors), but not sub-CUS (1 week exposure to stressors), induces depression-like behaviors and impairs these forms of eCB/CB1 receptor-mediated plasticity examined in the NAc core. Neither sub-CUS nor CUS altered the tissue contents of the eCBs, anandamide and 2-arachidonoylglycerol in the striatum. However, exposure to CUS, but not to sub-CUS, attenuated the depression of fEPSPs induced by the CB1 receptor agonist WIN 55 212-2. CUS exposure reduced the maximal effect without affecting the EC(50) of WIN 55 212-2 to induce fEPSP depression. Thus, impaired CB1 receptor function could account for CUS-induced deficiency in eCB signaling in the NAc. Both CUS-induced deficiency in eCB signaling and depression-like behaviors were reversed by in vivo administration of antidepressant fluoxetine. These results suggest that downregulation of eCB signaling in the NAc occurs after CUS and contributes to the pathophysiology of depression.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazines / pharmacology
  • Cannabinoid Receptor Modulators / deficiency*
  • Cannabinoid Receptor Modulators / physiology
  • Chronic Disease
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Endocannabinoids*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Stress, Psychological / metabolism*
  • Stress, Psychological / psychology


  • Benzoxazines
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Morpholines
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone