title: Modulation of anxiety-like behavior by the endocannabinoid 2-arachidonoylglycerol (2-AG) in the dorsolateral periaqueductal gray.
abstract: Anandamide and 2-arachidonoylglycerol (2-AG) are the two main endocannabinoids, exerting their effects by activating type 1 (CB1r) and type 2 (CB2r) cannabinoid receptors. Anandamide inhibits anxiety-like responses through the activation of CB1r in certain brain regions, including the dorsolateral periaqueductal gray (dlPAG). 2-AG also attenuates anxiety-like responses, although the neuroanatomical sites for these effects remained unclear. Here, we tested the hypothesis that enhancing 2-AG signaling in the dlPAG would induce anxiolytic-like effects. The mechanisms involved were also investigated. Male Wistar rats received intra-dlPAG injections of 2-AG, URB602 (inhibitor of the 2-AG hydrolyzing enzyme, mono-acylglycerol lipase--MGL), AM251 (CB1r antagonist) and AM630 (CB2r antagonist). The behavior was analyzed in the elevated plus maze after the following treatments. Exp. 1: vehicle (veh) or 2-AG (5 pmol, 50 pmol, and 500 pmol). Exp. 2: veh or URB602 (30 pmol, 100 pmol or 300 pmol). Exp. 3: veh or AM251 (100 pmol) followed by veh or 2-AG (50 pmol). Exp. 4: veh or AM630 (1000 pmol) followed by veh or 2-AG. Exp. 5: veh or AM251 followed by veh or URB602 (100 pmol). Exp. 6: veh or AM630 followed by veh or URB602. 2-AG (50 pmol) and URB602 (100 pmol) significantly increased the exploration of the open arms of the apparatus, indicating an anxiolytic-like effect. These behavioral responses were prevented by CB1r (AM251) or CB2r (AM630) antagonists. Our results showed that the augmentation of 2-AG levels in the dlPAG induces anxiolytic-like effects. The mechanism seems to involve both CB1r and CB2r receptors.
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: A F
authors.initials: AF
authors.lastname: Almeida-Santos
authors.forename: P H
authors.initials: PH
authors.lastname: Gobira
authors.forename: L C
authors.initials: LC
authors.lastname: Rosa
authors.forename: F S
authors.initials: FS
authors.lastname: Guimaraes
authors.forename: F A
authors.initials: FA
authors.lastname: Moreira
authors.forename: D C
authors.initials: DC
authors.lastname: Aguiar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D001095:Arachidonic Acids / Q000378:metabolism* / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000633:toxicity*; D063386:Cannabinoid Receptor Agonists / Q000633:toxicity*; D063387:Cannabinoid Receptor Antagonists; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism* / Q000633:toxicity*; D005989:Glycerides / Q000378:metabolism* / Q000633:toxicity*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D010487:Periaqueductal Gray / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D005989:Glycerides; D007211:Indoles; D010880:Piperidines; D011720:Pyrazoles; C501835:URB602; C103505:AM 251; C094503:glyceryl 2-arachidonate; C094023:iodopravadoline
keywords: 2-Arachidonoylglycerol (2-AG); Anxiety; Dorsolateral periaqueductal gray; Elevated plus maze; Endocannabinoids