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Endocannabinoids and Stress Resilience: Is Deficiency Sufficient to Promote Vulnerability?

  • Matthew N. Hill
    Correspondence
    Address correspondence to Matthew Hill, Ph.D., Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N4N1, Canada;
    Affiliations
    Hotchkiss Brain Institute, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Alberta, Canada
    Search for articles by this author
  • Francis S. Lee
    Affiliations
    Sackler Institute for Developmental Psychobiology, Department of Psychiatry, Weill Cornell Medical College, New York, New York
    Search for articles by this author
      Over the past 2 decades, there has been rapidly growing interest in the role of the endocannabinoid (eCB) system in the regulation of stress and emotional processes. Several lines of converging evidence provide strong evidence that eCB signaling is a key player in these processes. First, genetic ablation or pharmacologic antagonism of the cannabinoid type 1 receptor (CB1R) results in exaggerated neuroendocrine and behavioral responses to acute stress (
      • Morena M.
      • Patel S.
      • Bains J.S.
      • Hill M.N.
      Neurobiological interactions between stress and the endocannabinoid system.
      ). More so, sustained disruption of CB1R signaling produces an array of neurobiological changes consistent with alterations seen after chronic stress or in mood disorders, such as reductions in neurotrophin levels, neurogenesis and dendritic complexity, and increased levels of central neuroinflammation (
      • Beyer C.E.
      • Dwyer J.M.
      • Piesla M.J.
      • Platt B.J.
      • Shen R.
      • Rahman Z.
      • et al.
      Depression-like phenotype following chronic CB1 antagonism.
      ,
      • Hill M.N.
      • Hillard C.J.
      • McEwen B.S.
      Alterations in corticolimbic dendritic morphology and emotional behavior in cannabinoid CB1 receptor-deficient mice parallel the effects of chronic stress.
      ). Second, facilitation of eCB signaling can dampen the impact of both acute and chronic stress on almost every variable examined, including alterations in anxiety, reward sensitivity, hyperalgesia, morphologic changes in the amygdala, and hippocampal synaptic plasticity (
      • Morena M.
      • Patel S.
      • Bains J.S.
      • Hill M.N.
      Neurobiological interactions between stress and the endocannabinoid system.
      ). Third, the eCB system is highly sensitive to stress exposure. Specifically, under conditions of acute stress, the eCB system plays an important buffering role by limiting the magnitude of the stress response and facilitating recovery to basal function after cessation of stress exposure (
      • Morena M.
      • Patel S.
      • Bains J.S.
      • Hill M.N.
      Neurobiological interactions between stress and the endocannabinoid system.
      ). However, under conditions of chronic stress, the eCB system appears to “collapse” in the sense that CB1Rs downregulate and lose their ability to modulate the synaptic release of neurotransmitters, such as glutamate and gamma-aminobutyric acid (
      • Morena M.
      • Patel S.
      • Bains J.S.
      • Hill M.N.
      Neurobiological interactions between stress and the endocannabinoid system.
      ).
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      Linked Article

      • Anxiety, Stress, and Fear Response in Mice With Reduced Endocannabinoid Levels
        Biological PsychiatryVol. 79Issue 10
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          Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α).
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