title: Role of the endocannabinoid 2-arachidonoylglycerol in aversive responses mediated by the dorsolateral periaqueductal grey.
abstract: 2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks. The present work verified if facilitation of 2-AG signalling in the dlPAG counteracts panic-like responses induced by local chemical stimulation. Intra-dlPAG injection of 2-AG prevented panic-like response induced by the excitatory amino acid N-methyl-d-aspartate (NMDA). This effect was mimicked by the 2-AG hydrolysis inhibitor (MAGL preferring inhibitor) URB602. The anti-aversive effect of URB602 was reversed by the CB1 receptor antagonist, AM251. Additionally, a combination of sub-effective doses of 2-AG and URB602 also prevented NMDA-induced panic-like response. Finally, immunofluorescence assay showed a significant increase in c-Fos positive cells in the dlPAG after local administration of NMDA. This response was also prevented by URB602. These data support the hypothesis that 2-AG participates in anti-aversive mechanisms in the dlPAG and reinforce the proposal that facilitation of endocannabinoid signalling could be a putative target for developing additional treatments against panic and other anxiety-related disorders.
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: P H
authors.initials: PH
authors.lastname: Gobira
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.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP 14049-900, Brazil; Center of Interdisciplinary Research of Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: F S
authors.initials: FS
authors.lastname: Guimaraes
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: F A
authors.initials: FA
authors.lastname: Moreira
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: D C
authors.initials: DC
authors.lastname: Aguiar
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005989:Glycerides / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate; D016584:Panic Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C501835:URB602; C103505:AM 251; D016202:N-Methylaspartate; C094503:glyceryl 2-arachidonate
keywords: 2AG; Aversive reactions; Endocannabinoids; Panic; Periaqueductal grey