Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

Abstract

Recent reports have demonstrated that disruption of CB 1 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 (À/À) 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, FAAHcompromised mice also exhibited a significant increase in acquisition rate. The CB 1 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 CB 1 receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, D 9 -tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB 1 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.

The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat

“…Furthermore, at a dose of 5 mg/kg CBD neither affected the acquisition nor retrieval of a floor-amphetamine association in a conditioned place preference task (Parker et al 2004a) or of a flavor-lithium association in a conditioned taste avoidance task (Parker et al 2002). Finally, Varvel et al (2007) reported that mice pre-treated with the FAAH inhibitor, OL-135, as well as FAAH knockout mice with elevated central AEA levels, did not display memory impairment or motor disruption in a spatial memory task (Morris water maze); in fact, the FAAH knockouts displayed a significant increase in acquisition rate.…”

Cannabinoids modulate hippocampal memory and plasticity

“…CB1-deficient mice show impaired auditory fear extinction, with unaffected memory acquisition and consolidation (Marsicano et al, 2002). Additionally, there are reports of facilitated fear extinction following systemic cannabinoid activation (Chhatwal et al, 2005;Pamplona et al, , 2008 although several reports failed to show accelerated extinction following the administration of cannabinoid agonists WIN55,212-2 and tetrahydrocannabinol (THC; Chhatwal et al, 2005;Kobilo et al, 2007;Varvel et al, 2007).…”

The Endogenous Cannabinoid System Modulates Nicotine Reward and Dependence

“…All the genetically modified mice used in these studies were backcrossed 13 generations onto a C57BL/6 background. The CB 1 KO mice were derived from CB 1 heterozygote parents, and the FAAH KO mice were derived from congenic FAAH KO parents (Varvel et al, 2007;Wise et al, 2007). Separate groups of adult male C57BL/6J mice obtained from The Jackson Laboratory (Bar Harbor, ME) were used for all drug experiments.…”