title: Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity.
abstract: The endocannabinoid ligand 2-arachidonoylglycerol (2-AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant- and anxiolytic-like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive-like behaviors and decreased the number of bromodeoxyuridine-labeled neural progenitor cells and doublecortin-positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long-term potentiation (LTP) in the DG known to be neurogenesis-dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS-exposed mice. These results suggest that enhanced adult neurogenesis and long-term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant- and anxiolytic-like behavioral effects of JZL184.
authors.affiliation: Department of Geriatrics, Qi-Lu Hospital of Shandong University, Key Laboratory of Proteomics of Shandong Province, Jinan Shandong, China.|Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Liu
authors.affiliation: The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.affiliation: Department of Sports Physiology, Beijing Sport University, Beijing 100084, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Geriatrics, Qi-Lu Hospital of Shandong University, Key Laboratory of Proteomics of Shandong Province, Jinan Shandong, China.
authors.forename: Hai-Qing
authors.initials: HQ
authors.lastname: Gao
authors.affiliation: The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Qing-Song
authors.initials: QS
authors.lastname: Liu
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D052117:Benzodioxoles / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000378:metabolism*; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology*; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology*; D063388:Endocannabinoids / Q000037:antagonists & inhibitors*; D005989:Glycerides / Q000037:antagonists & inhibitors*; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology*; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases
keywords: CB1 receptor; chronic unpredictable stress; depression; endocannabinoid; neurogenesis