Complex interaction between anandamide and the nitrergic system in the dorsolateral periaqueductal gray to modulate anxiety-like behavior in rats

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 e...

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Published in:	Neuropharmacology Vol. 75; pp. 86 - 94
Main Authors:	Lisboa, S.F., Magesto, A.C., Aguiar, J.C., Resstel, L.B.M., Guimarães, F.S.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-12-2013
Subjects:	Anandamide Animals Anxiety Anxiety - drug therapy Anxiety - metabolism Apomorphine - analogs & derivatives Apomorphine - pharmacology Arachidonic Acids - therapeutic use Bicuculline - pharmacology Cannabinoid Receptor Agonists - therapeutic use Disease Models, Animal Dose-Response Relationship, Drug Endocannabinoids - therapeutic use Enzyme Inhibitors - pharmacology GABA GABA-A Receptor Antagonists - pharmacology Glutamate Male Maze Learning - drug effects Nitric oxide Nitric Oxide Synthase - metabolism Oxadiazoles - pharmacology Periaqueductal gray Periaqueductal Gray - drug effects Periaqueductal Gray - physiology Piperidines - pharmacology Polyunsaturated Alkamides - therapeutic use Pyrazoles - pharmacology Quinoxalines - pharmacology Rats Rats, Wistar Receptor, Cannabinoid, CB1 GABA Periaqueductal gray Anxiety Glutamate Nitric oxide Anandamide
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Summary:	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. •Combination of AEA and NO inhibitors induced anxiolytic or no behavioral effect.•Anxiolytic effect after combination of low or high doses involves CB1 receptors.•Anxiolytic effect after combination of low doses does not involve GABAA activation.•Anxiolytic effect after combination of high doses depends on GABA synthesis.•Anxiolytic effect after combination of high doses is mediated by GABAA receptors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-3908 1873-7064
DOI:	10.1016/j.neuropharm.2013.07.008