title: Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats.
abstract: Individuals who experience life-threatening psychological trauma are at risk of developing a series of chronic neuropsychiatric pathologies that include generalized anxiety, depression, and drug addiction. The endocannabinoid system has been implicated in the modulation of these responses by regulating the activity of the amygdala and the hypothalamic-pituitary-adrenal axis. However, the relevance of this signaling complex to the long-term consequences of traumatic events is unclear. Here we use an animal model of predatory stress-induced anxiety-like behavior to investigate the role of the endocannabinoid system in the development of persistent anxiety states. Our main finding is that rats exposed to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a life-threatening stimulus for rodents, display a marked and selective increase in the mobilization of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the amygdala. This effect lasts for at least 14 days after the stress has occurred. In addition, systemic or local pharmacological inhibition of monoacylglycerol lipase (MGL)-a lipid hydrolase that degrades 2-AG in presynaptic nerve terminals-elevates 2-AG levels and suppresses the anxiety-like behavior elicited by exposure to TMT. The results suggest that predator threat triggers long-term changes in 2-AG-mediated endocannabinoid signaling in the amygdala, and that pharmacological interventions targeting MGL might provide a therapeutic strategy for the treatment of chronic brain disorders initiated by trauma.
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
authors.forename: Miki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università di Siena, Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università di Siena, Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.|Department of Pharmacology, University of California, Irvine, CA, USA.|Department of Biological Chemistry, University of California, Irvine, CA, USA.|Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism*; D052117:Benzodioxoles / Q000008:administration & dosage; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005989:Glycerides / Q000378:metabolism*; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000139:chemically induced / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage
chemical_list: C411827:2,5-dihydro-2,4,5-trimethylthiazoline; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; D013844:Thiazoles; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases