1. ¹Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA
2. ²Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, CA, USA

Correspondence: Dr AH Lichtman, Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, PO Box 980613, Richmond, VA 23298-0613, USA. Tel: +1 804 828 8480; Fax: +1 804 828 2117; E-mail: alichtma@vcu.edu

Received 10 April 2006; Revised 29 August 2006; Accepted 1 September 2006; Published online 18 October 2006.

Abstract

Recent reports have demonstrated that disruption of CB₁ receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB₁ receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB₁ receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, ⁹-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB₁ receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.