title: 2-arachidonoylglycerol signaling impairs short-term fear extinction.
abstract: Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor-dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over-conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2-AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure.
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.|Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Hartley
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, MD, USA.
authors.forename: O
authors.initials: O
authors.lastname: Gunduz-Cinar
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Halladay
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, MD, USA.
authors.forename: O
authors.initials: O
authors.lastname: Bukalo
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Holmes
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.|Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Patel
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063388:Endocannabinoids / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D005989:Glycerides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate