Adolescent chronic mild stress alters hippocampal CB1 receptor-mediated excitatory neurotransmission and plasticity

Neuroscience. 2013 Dec 3;253:444-54. doi: 10.1016/j.neuroscience.2013.08.066. Epub 2013 Sep 13.


Endocannabinoids (eCBs) are involved in the stress response and alterations in eCB signaling may contribute to the etiology of mood disorders. Exposure to chronic mild stress (CMS), a model of depression, produces downregulation of the cannabinoid 1 (CB1) receptor in the hippocampus of male rats. However, it is unknown how this stress-induced change in CB1 levels affects eCB-mediated neurotransmission. In vitro, field potential recordings from CMS-exposed (21-days) rats were performed to assess the effects of stress on eCB-regulated glutamatergic neurotransmission in/on hippocampal area CA1. We observed that application of the CB1 agonist, WIN 55,212-5 (1 μM), in stress animals resulted in a ∼135% increase in excitatory neurotransmission, whereas CB1 activation in non-stress animals leads to a ∼30% decrease. However, during blockade of GABA(A) neurotransmission with picrotoxin, CB1 activation yielded a ∼35% decrease in stress animals. These findings indicate that CMS does not directly affect glutamatergic neurotransmission. Rather, CMS sensitizes CB1 function on GABAergic terminals, leading to less inhibition and an increase in excitatory neurotransmission. This finding is reinforced in that induction of weak long-term-potentiation (LTP) is enhanced in CMS-exposed animals compared to controls and this enhancement is CB1-dependent. Lastly, we observed that the LTP-blocking property of WIN 55,212-5 shifts from being glutamate-dependent in non-stress animals to being GABA-dependent in stress animals. These results effectively demonstrate that CMS significantly alters hippocampal eCB-mediated neurotransmission and synaptic plasticity.

Keywords: 2-AG; 2-arachidonoyl-glycerol; ACSF; AEA; ANOVA; CB; CB1 receptor; CCK; CMS; CRS; DMSO; DSI; GC; HPA; LTP; MANOVAs; NS; PND; PTSD; PTX; S; TBS; analysis of variance; artificial cerebrospinal fluid; cannabinoid; cholecystokinin; chronic mild stress; chronic restraint stress; depolarization-induced-suppression of inhibition; depression; dimethyl sulfoxide; eCBs; endocannabinoid/endovanniloid anandamide; endocannabinoids; glucocorticoid; hippocampus; hypothalamic–pituitary–adrenal; long-term-potentiation; multivariate ANOVA; non-stress; picrotoxin; post natal day; post-traumatic-stress-disorder; stress; theta-burst stimulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzoxazines / pharmacology
  • Chronic Disease
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / drug effects*
  • Excitatory Postsynaptic Potentials / physiology
  • GABA Antagonists / pharmacology
  • Gene Expression Regulation / physiology*
  • Hippocampus / metabolism*
  • In Vitro Techniques
  • Male
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Picrotoxin / pharmacology
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Stress, Psychological / pathology*
  • Synaptic Transmission / drug effects


  • Benzoxazines
  • GABA Antagonists
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Picrotoxin
  • 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