Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats

• Published in: European neuropsychopharmacology Vol. 18; no. 12; pp. 849 - 859
• Main Authors: Bitencourt, Rafael M, Pamplona, Fabrício A, Takahashi, Reinaldo N
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2008
• Subjects: AM404; Analysis of Variance; Animals; Anti-Anxiety Agents - pharmacology; Anxiety; Arachidonic Acids - pharmacology; Behavior, Animal - drug effects; Cannabidiol; Cannabidiol - antagonists & inhibitors; Cannabidiol - pharmacology; Cannabinoid; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Conditioning (Psychology) - drug effects; Dose-Response Relationship, Drug; Drug Administration Schedule; Extinction; Extinction, Psychological - drug effects; Fear; Fear conditioning; Freezing Reaction, Cataleptic - drug effects; Injections, Intraventricular - methods; Internal Medicine; Male; Maze Learning - drug effects; Piperidines - pharmacology; Psychiatry; Pyrazoles - pharmacology; Rats; Rats, Wistar; TRPV Cation Channels - antagonists & inhibitors; Cannabidiol; Anxiety; AM404; Cannabinoid; Extinction; Fear conditioning
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2008.07.001

Abstract The present study investigated the central effects of the eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid cannabidiol (CBD) on the extinction of contextual fear memories in rats. Rats were conditioned and 24 h later subjected to three consecutive 9-min non-reinforced exposures to the conditioning context (extinction sessions, 24 h intervals). AM404 or CBD was injected i.c.v. 5 min before each extinction session and a 3-min drug-free test of contextual memory was performed 24 h after the last extinction session. AM404 (1.0 µg/µl, i.c.v.) and CBD (2.0 µg/µl, i.c.v.) facilitated extinction of contextual fear memory, with persistent effects. These responses were antagonized by the CB1-selective antagonist SR141716A (0.2 mg/kg, i.p.), but not by the TRPV1-selective antagonist capsazepine (5.0 µg/µl, i.c.v.). The effect of the anxiolytic drug Diazepam (DZP) on the extinction of contextual fear memory was also investigated. In contrast with the CBD and AM404 results, DZP induced a general reduction in the expression of conditioned freezing. Both AM404 and CBD induced anti-anxiogenic effect in the fear-potentiated plus-maze test, whereas DZP was anxiolytic in conditioned and unconditioned rats. In conclusion, CBD, a non-psychoactive phytocannabinoid could be an interesting pharmacological approach to reduce the anxiogenic effects of stress and promote the extinction of fear memories.