Advertisement

The Anxiolytic Actions of 2-Arachidonoylglycerol: Converging Evidence From Two Recent Genetic Endocannabinoid Deficiency Models

  • Sachin Patel
    Correspondence
    Address correspondence to Sachin Patel, M.D., Ph.D., Departments of Psychiatry and Molecular Physiology and Biophysics, MRB IV (Langford), Room 8425B, Vanderbilt University Medical Center, Nashville, TN 37232
    Affiliations
    Departments of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee

    Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee

    Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee

    Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee
    Search for articles by this author
  • Brian C. Shonesy
    Affiliations
    Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
    Search for articles by this author
  • Rebecca J. Bluett
    Affiliations
    Departments of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee
    Search for articles by this author
  • Danny G. Winder
    Affiliations
    Departments of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee

    Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee

    Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee

    Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee
    Search for articles by this author
  • Roger J. Colbran
    Affiliations
    Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee

    Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee

    Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee
    Search for articles by this author
      The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is a lipid-signaling molecule synthesized in the central nervous system primarily by diacylglycerol lipase alpha (DAGLA) that exerts biological actions primarily via activation of CB1 type cannabinoid receptors. CB1 is the primary target of Δ9-tetrahydrocannabinol, and anxiety reduction and tension relief have been reported as primary motives for chronic cannabis use (
      • Hyman S.M.
      • Sinha R.
      Stress-related factors in cannabis use and misuse: Implications for prevention and treatment.
      ). Consistent with this, pharmacologic augmentation of 2-AG levels reduces anxiety-like and depressive behaviors, and 2-AG levels increase in the amygdala in response to repeated stress exposure, suggesting a physiologic role for this signaling system in buffering against the development of stress-induced pathology (
      • Hill M.N.
      • Patel S.
      Translational evidence for the involvement of the endocannabinoid system in stress-related psychiatric illnesses.
      ). However, whether 2-AG deficiency states could contribute to the pathologic expression of anxiety and depressive behaviors is unknown. In the past 6 months, two studies, by Shonesy et al. (
      • Shonesy B.C.
      • Bluett R.J.
      • Ramikie T.S.
      • Baldi R.
      • Hermanson D.J.
      • Kingsley P.J.
      • et al.
      Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation.
      ) and Jenniches et al. (
      • Jenniches I.
      • Ternes S.
      • Albayram O.
      • Otte D.M.
      • Bach K.
      • Bindila L.
      • et al.
      Anxiety, stress and fear response in mice with reduced endocannabinoid levels.
      ), provide compelling converging evidence that 2-AG deficiency is causally related to the expression of anxiety and depressive-like behavior. Dagla−/− mice, which showed dramatically reduced central 2-AG levels, were created by Shonesy et al. (targeting exon 8) and by Jenniches et al. (targeting exon 1). Both lines of Dagla−/− mice showed prominent basal anxiety and depressive-like behaviors in various substantially overlapping behavioral assays (Table 1), although Jenniches et al. (
      • Jenniches I.
      • Ternes S.
      • Albayram O.
      • Otte D.M.
      • Bach K.
      • Bindila L.
      • et al.
      Anxiety, stress and fear response in mice with reduced endocannabinoid levels.
      ) additionally found that conditioned fear extinction was impaired in Dagla−/− mice (Table 1). The remarkable concordance of the findings from different mouse lines and different laboratories provides strong support for the hypothesis that 2-AG signaling plays a key role in the regulation of emotional behavior and stress responsivity.
      Table 1Comparative Behavioral Profile of Two Independently Generated Lines of Dagla−/− Mice
      Dagla−/− Mice Shonesy et al., 2014 (
      • Shonesy B.C.
      • Bluett R.J.
      • Ramikie T.S.
      • Baldi R.
      • Hermanson D.J.
      • Kingsley P.J.
      • et al.
      Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation.
      )
      Jenniches et al., 2016 (
      • Jenniches I.
      • Ternes S.
      • Albayram O.
      • Otte D.M.
      • Bach K.
      • Bindila L.
      • et al.
      Anxiety, stress and fear response in mice with reduced endocannabinoid levels.
      )
      Exon Target 8 1
      Sex Analysis Separate Combined
      Breeding Scheme Het × Het KO × KO
      Motor Function
       Open field (locomotion) NC
      Unless indicated, behavioral phenotype in this column observed in both sexes when analyzed separately.
      NC
       Rotarod NC
       Home cage locomotion NC
      Anxiety
       Open field thigmotaxis ↑ (F)
      NC (M)
       Light/dark (dark preference)
       NIH assay (latency to drink)
       Zero maze (DT in open arms)
      Unpublished data.
       Fear extinction
      Depression
       Tail suspension (immobility) NC
       Forced swim (immobility)
       Sucrose preference ↓ (F) NC
      NC (M)
      Social Behavior
       Maternal neglect
       Social preference NC
      DT, distance traveled; F, female; Het, heterozygous; KO, knockout; M, male; NC, not changed; NIH, novelty-induced hypophagia; —, not done.
      a Unless indicated, behavioral phenotype in this column observed in both sexes when analyzed separately.
      b Unpublished data.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hyman S.M.
        • Sinha R.
        Stress-related factors in cannabis use and misuse: Implications for prevention and treatment.
        J Subst Abuse Treat. 2009; 36: 400-413
        • Hill M.N.
        • Patel S.
        Translational evidence for the involvement of the endocannabinoid system in stress-related psychiatric illnesses.
        Biol Mood Anxiety Disord. 2013; 3: 19
        • Shonesy B.C.
        • Bluett R.J.
        • Ramikie T.S.
        • Baldi R.
        • Hermanson D.J.
        • Kingsley P.J.
        • et al.
        Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation.
        Cell Rep. 2014; 9: 1644-1653
        • Jenniches I.
        • Ternes S.
        • Albayram O.
        • Otte D.M.
        • Bach K.
        • Bindila L.
        • et al.
        Anxiety, stress and fear response in mice with reduced endocannabinoid levels.
        Biol Psychiatry. 2016; 79: 858-868
        • Hill M.N.
        • Miller G.E.
        • Carrier E.J.
        • Gorzalka B.B.
        • Hillard C.J.
        Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress.
        Psychoneuroendocrinology. 2009; 34: 1257-1262
        • Hill M.N.
        • Bierer L.M.
        • Makotkine I.
        • Golier J.A.
        • Galea S.
        • McEwen B.S.
        • et al.
        Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks.
        Psychoneuroendocrinology. 2013; 38: 2952-2961

      Linked Article

      • Reply to: The Anxiolytic Actions of 2-Arachidonoylglycerol: Converging Evidence From Two Recent Genetic Endocannabinoid Deficiency Models
        Biological PsychiatryVol. 79Issue 10
        • Preview
          Two recent independent studies by Shonesy et al. (1) and Jenniches et al. (2) investigated mice lacking diacylglycerol lipase alpha (DAGLα), a key enzyme for the formation of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid in the brain. Both lines showed strongly reduced 2-AG levels in most brain areas and very similar anxiety and depressive-like behavioral phenotypes. These findings are in agreement with the previous observation that 2-AG produces antidepressant and anxiolytic effects (3,4) and that long-term antidepressant treatment leads to a significant increase in 2-AG levels in different brain areas (5).
        • Full-Text
        • PDF
      • Deep Brain Stimulation of the Basolateral Amygdala for Treatment-Refractory Posttraumatic Stress Disorder
        Biological PsychiatryVol. 79Issue 10
        • Preview
          Posttraumatic stress disorder (PTSD) affects approximately 6.8% of the U.S. population in their lifetime (1). Current treatments include antidepressant medications and psychotherapy, but a significant number of patients remain refractory. Treatment-refractory PTSD is associated with substance use disorders (2), general medical illnesses (3), and suicide (4). Treatment refractoriness is due at least in part to failure of fear extinction, rendering exposure therapy ineffective. Fear extinction is mediated by the interaction of the basolateral nucleus of the amygdala (BLn) and the medial prefrontal cortex (5).
        • Full-Text
        • PDF