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Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 2014 Jun;39(7):1763-76

Date

01/31/2014

Pubmed ID

24476943

Pubmed Central ID

PMC4023150

DOI

10.1038/npp.2014.24

Scopus ID

2-s2.0-84900565127 (requires institutional sign-in at Scopus site)   107 Citations

Abstract

The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization-induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB1 receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling.

Author List

Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, Zhang HT, Cravatt BF, Liu QS

Author

Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antidepressive Agents
Benzodioxoles
Dependovirus
Depression
Disease Models, Animal
Enzyme Inhibitors
Exploratory Behavior
Feeding Behavior
Food Preferences
Hippocampus
Male
Mice
Mice, Inbred C57BL
Monoacylglycerol Lipases
Neurons
Piperidines
Stress, Psychological
Sucrose
Swimming
TOR Serine-Threonine Kinases