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

      Two recent independent studies by Shonesy et al. (
      • Shonesy B.C.
      • Bluett R.J.
      • Ramikie T.S.
      • Báldi 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.
      ) 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 (
      • Zhong P.
      • Wang W.
      • Pan B.
      • Liu X.
      • Zhang Z.
      • Long J.Z.
      • et al.
      Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling.
      ,
      • Zhang Z.
      • Wang W.
      • Zhong P.
      • Liu S.J.
      • Long J.Z.
      • Zhao L.
      • et al.
      Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity.
      ) and that long-term antidepressant treatment leads to a significant increase in 2-AG levels in different brain areas (
      • Smaga I.
      • Bystrowska B.
      • Gawlinski D.
      • Pomierny B.
      • Stankowicz P.
      • Filip M.
      Antidepressants and changes in concentration of endocannabinoids and N-acylethanolamines in rat brain structures.
      ). Thus, 2-AG seems to play a key role in the modulation of the affective state and stress-related behaviors.
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      References

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        • Bluett R.J.
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        • Báldi R.
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        Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation.
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        • Jenniches I.
        • Ternes S.
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        Anxiety, stress and fear response in mice with reduced endocannabinoid levels.
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        • Wang W.
        • Pan B.
        • Liu X.
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        Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling.
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        Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity.
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        • Bystrowska B.
        • Gawlinski D.
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        The anxiolytic actions of 2-arachidonoylglycerol: Converging evidence from two recent genetic endocannabinoid deficiency models.
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      Linked Article

      • The Anxiolytic Actions of 2-Arachidonoylglycerol: Converging Evidence From Two Recent Genetic Endocannabinoid Deficiency Models
        Biological PsychiatryVol. 79Issue 10
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          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 (1). 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 (2).
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