title: Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses.
abstract: The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB1cannabinoid receptor (CB1R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB1R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression-like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants.
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.|Department of Psychiatry, Xijing Hospital, Xi' an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Gu
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Duan
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Kesner
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Blaskovits
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Xi' an, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Anatomy, Histology and Embryology, Fourth Military Medical University, Xi' an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Tong
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Biology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Harris
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mackie
authors.affiliation: Department of Anatomy, Histology and Embryology, Fourth Military Medical University, Xi' an, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Xijing Hospital, Xi' an, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Departments of Cell Biology and Anatomy & Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
authors.forename: M N
authors.initials: MN
authors.lastname: Hill
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.|Department of Psychiatry, Xijing Hospital, Xi' an, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001095:Arachidonic Acids; D052117:Benzodioxoles / Q000378:metabolism* / Q000627:therapeutic use; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism / Q000627:therapeutic use; D059330:GABAergic Neurons / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: C000601471:1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo(d)(1,3)dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate; D000928:Antidepressive Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; C534333:JZL 184; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D008994:Monoacylglycerol Lipases