title: Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation.
abstract: Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.
authors.affiliation: Department of Psychiatry, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Sumislawski
authors.forename: Teniel S
authors.initials: TS
authors.lastname: Ramikie
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects / Q000502:physiology; D000679:Amygdala / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000502:physiology; D009924:Organ Culture Techniques; D010880:Piperidines / Q000494:pharmacology; D013315:Stress, Psychological / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases