Anxiolytic-like properties of the anandamide transport inhibitor AM404.
The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg(-1), intraperitoneal (i.p.)) exerted dose-dependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB(1) cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB(1) cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg(-1), i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs.
Department of Psychiatry and Human Behavior, Center for Drug Discovery, University of California, Irvine, CA 92697-4625, USA.
Marco
M
Bortolato
Patrizia
P
Campolongo
Regina Anne
RA
Mangieri
Maria Luisa
ML
Scattoni
Roberto
R
Frau
Viviana
V
Trezza
Giovanna
G
La Rana
Roberto
R
Russo
Antonio
A
Calignano
Gian Luigi
GL
Gessa
Vincenzo
V
Cuomo
Daniele
D
Piomelli
D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001010:Anxiety, Separation / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D004195:Disease Models, Animal; D063388:Endocannabinoids; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D000077285:Rimonabant
D014151:Anti-Anxiety Agents; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002352:Carrier Proteins; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide