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Hippocampus. 2015 Jan;25(1):16-26. doi: 10.1002/hipo.22344. Epub 2014 Aug 27.

Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity.

Author information

1
Department of Geriatrics, Qi-Lu Hospital of Shandong University, Key Laboratory of Proteomics of Shandong Province, Jinan Shandong, China.
2
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
3
The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
4
Department of Sports Physiology, Beijing Sport University, Beijing 100084, China.
#
Contributed equally

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.

KEYWORDS:

CB1 receptor; chronic unpredictable stress; depression; endocannabinoid; neurogenesis

PMID:
25131612
PMCID:
PMC4517601
DOI:
10.1002/hipo.22344
[Indexed for MEDLINE]
Free PMC Article

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