Anxiolytic effects in mice of a dual blocker of fatty acid amide hydrolase and transient receptor potential vanilloid type-1 channels.
The endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), and the transient receptor potential vanilloid type-1 (TRPV1) channel are new targets for the development of anxiolytic drugs. We studied the effect on anxiety-like behavior in the elevated plus maze of a dual FAAH/TRPV1 blocker, N-arachidonoyl-serotonin (AA-5-HT). In male C57BL/6J mice, acute intraperitoneal administration of AA-5-HT (0.1-2.5 mg/kg) increased both the time spent and the number of entries in the open arm, while being inactive at the highest dose tested (5 mg/kg). AA-5-HT was more potent than selective blockers of FAAH or TRPV1 (URB597 and SB366791, respectively). In male Swiss mice, AA-5-HT had to be administered chronically to observe an anxiolytic effect at an intermediate dose (2.5 mg/kg), the highest dose (5 mg/kg) being anxiogenic, and 1 mg/kg being ineffective. In both strains, the anxiolytic effects of AA-5-HT were paralleled by elevation of brain endocannabinoid levels and were reversed by per se inactive doses of the cannabinoid receptors of type-1 (CB(1)) receptor antagonist AM251, or the TRPV1 agonist, olvanil. Immunohistochemical localization of CB(1) and TRPV1 receptors was observed in mouse prefrontal cortex, nucleus accumbens, amygdala, and hippocampus. Simultaneous 'indirect' activation of CB(1) receptors following FAAH inhibition, and antagonism at TRPV1 receptors might represent a new therapeutic strategy against anxiety.
Micale
Vincenzo
V
Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania, Italy.
Cristino
Luigia
L
Tamburella
Alessandra
A
Petrosino
Stefania
S
Leggio
Gian Marco
GM
Drago
Filippo
F
Di Marzo
Vincenzo
V
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D001095:Arachidonic Acids / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects*; D008297:Male; D051379:Mice / Q000378:metabolism / Q000523:psychology; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000813:Anilides; D014151:Anti-Anxiety Agents; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002211:Capsaicin; D002219:Carbamates; D002934:Cinnamates; D003975:Diazepam; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D012701:Serotonin; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; C493921:TRPV1 protein, mouse; C114007:arachidonoylserotonin; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C054256:olvanil