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• W1040661821 abstract "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 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 Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar ). 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 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 Crossref PubMed Google Scholar ). 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. ( 3 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 Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar ) and Jenniches et al. ( 4 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 Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar ), 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. ( 4 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 Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar ) 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 ( 3 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 Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar ) Jenniches et al., 2016 ( 4 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 Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar ) Exon Target 8 1 Sex Analysis Separate Combined Breeding Scheme Het × Het KO × KO Motor Function Open field (locomotion) NC a 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) ↑ b 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. Open table in a new tab DT, distance traveled; F, female; Het, heterozygous; KO, knockout; M, male; NC, not changed; NIH, novelty-induced hypophagia; —, not done. Reply to: The Anxiolytic Actions of 2-Arachidonoylglycerol: Converging Evidence From Two Recent Genetic Endocannabinoid Deficiency ModelsBiological PsychiatryVol. 79Issue 10PreviewTwo 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 DisorderBiological PsychiatryVol. 79Issue 10PreviewPosttraumatic 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" @default.
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• W1040661821 title "The Anxiolytic Actions of 2-Arachidonoylglycerol: Converging Evidence From Two Recent Genetic Endocannabinoid Deficiency Models" @default.
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