title: Complex interaction between anandamide and the nitrergic system in the dorsolateral periaqueductal gray to modulate anxiety-like behavior in rats.
abstract: Stimulation of cannabinoid CB1 receptors or inhibition of nitric oxide synthase (NOS) in the dorsolateral periaqueductal gray (dlPAG) decreases anxiety-like behavior. Moreover, activation of CB1 receptors attenuates flight responses induced by nitric oxide (NO) donors in the dlPAG, suggesting that endocannabinoids and NO could interact to control defensive responses such as anxiety-like behavior. To test this hypothesis male Wistar rats received intra-dlPAG microinjections of anandamide (AEA) or NO inhibitors and were tested in the elevated plus maze (EPM). Combined administration of low and ineffective doses of AEA and the NO scavenger (c-Ptio), the nNOS inhibitor (NPA) or the soluble guanylate cyclase inhibitor (ODQ) induced anxiolytic-like effects. The CB1 receptor antagonist AM251, but not the GABAA receptor antagonist bicuculline, attenuated the effect induced by AEA+c-Ptio combination. No effect, however, was found when anxiolytic doses of these same drugs were administered together. Combination of higher, ineffective doses of AEA and c-Ptio, NPA or ODQ was again anxiolytic. The effect of the former combination was prevented by low and ineffective doses of the GABAA receptor antagonist bicuculline or the GABA synthesis inhibitor L-allilglycine, suggesting that they depend on GABAA-mediated neurotransmission. AM251 was also able to attenuate this effect, indicating that in the presence of NO inhibition, the resultant anxiolytic-like effect could be due to AEA action on CB1 receptors. The present results suggest that the AEA and nitrergic systems exert a complex functional interaction in the dlPAG to modulate anxiety behavior, probably interfering, in addition to glutamate, also with GABAergic mechanisms.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil. Electronic address: sabrinalisboa@usp.br.
authors.forename: S F
authors.initials: SF
authors.lastname: Lisboa
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Magesto
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: J C
authors.initials: JC
authors.lastname: Aguiar
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: L B M
authors.initials: LB
authors.lastname: Resstel
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: F S
authors.initials: FS
authors.lastname: Guimarães
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism; D001058:Apomorphine / Q000031:analogs & derivatives / Q000494:pharmacology; D001095:Arachidonic Acids / Q000627:therapeutic use*; D001640:Bicuculline / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1
chemical_list: C425777:10,11-dihydroxy-N-n-propylnorapomorphine; C494582:1H-(1,2,3)oxadiazolo(4,4-a)quinoxalin-1-one; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D058787:GABA-A Receptor Antagonists; D010069:Oxadiazoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011810:Quinoxalines; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D019001:Nitric Oxide Synthase; D001058:Apomorphine; C078814:anandamide; D001640:Bicuculline
keywords: Anandamide; Anxiety; GABA; Glutamate; Nitric oxide; Periaqueductal gray