Journal Article

Anxiolytic-Like Properties of the Anandamide Transport Inhibitor AM404

Scattoni, Maria Luisa, Bortolato, Marco, Campolongo, Patrizia, Cuomo, Vincenzo, Frau, Roberto, Gessa, Gian Luigi, Mangieri, Regina Anne, La Rana, Giovanna, Piomelli, Daniele, Russo, Roberto, Calignano, Antonio, Trezza, Viviana

2006

Overview

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.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: Animals / Animals, Newborn / Anti-Anxiety Agents - pharmacology / Anxiety / Anxiety Disorders - drug therapy / Anxiety Disorders - metabolism / Anxiety Disorders - physiopathology / Anxiety, Separation - drug therapy / Anxiety, Separation - metabolism / Anxiety, Separation - physiopathology / Arachidonic Acids - metabolism / Arachidonic Acids - pharmacology / Behavior, Animal - drug effects / Behavior, Animal - physiology / Biological and medical sciences / Brain - drug effects / Brain - metabolism / Brain - physiopathology / Cannabinoid Receptor Modulators - metabolism / Carrier Proteins - antagonists & inhibitors / Carrier Proteins - drug effects / Chromatography / Disease Models, Animal / Endocannabinoids / Laboratory animals / Male / Maze Learning - drug effects / Maze Learning - physiology / Medical sciences / Neural Inhibition - drug effects / Neural Inhibition - physiology / Neuropharmacology / Pharmacology / Pharmacology. Drug treatments / Piperidines - pharmacology / Polyunsaturated Alkamides - metabolism / Psycholeptics: tranquillizer, neuroleptic / Psychology. Psychoanalysis. Psychiatry / Psychopharmacology / Pyrazoles - pharmacology / Rats / Rats, Sprague-Dawley / Rats, Wistar / Receptor, Cannabinoid, CB1 - agonists / Receptor, Cannabinoid, CB1 - antagonists & inhibitors / Receptor, Cannabinoid, CB1 - metabolism / Reflex, Startle - drug effects / Reflex, Startle - physiology