Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats.

Leigh V Panlilio,Shakiru O Alapafuja,Alexandros Makriyannis,Daniele Piomelli,Steven R Goldberg,Tiziano Bandiera,Eric B Thorndike,Spyros P Nikas,Benjamin F Cravatt,Zuzana Justinova

doi:10.1007/s00213-015-4140-6

Abstract

Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandamide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized. We determined the effects of five structurally different FAAH inhibitors in an animal model of working memory known to be sensitive to impairment by delta-9 tetrahydrocannabinol (THC). A delayed nonmatching-to-position procedure was used in rats. Illuminated nosepoke holes were used to provide sample cues (left versus right) and record responses (correct versus incorrect) after delays ranging from 0 to 28s. Various test drugs were given acutely up to two times per week before daily sessions. One FAAH inhibitor, AM3506 (3mg/kg), decreased accuracy in the memory task. Four other FAAH inhibitors (URB597, URB694, PF-04457845, and ARN14633) and a monoacylglycerol lipase inhibitor (JZL184, which blocks the degradation of the endocannabinoid 2-arachidonoylglycerol) had no effect. Testing of AM3506 in combination with antagonists for receptors known to be affected by anandamide and other fatty acid amides indicated that the impairment induced by AM3506 was mediated by cannabinoid CB1 receptors, and not by alpha-type peroxisome proliferator-activated receptors (PPAR-alpha) or vanilloid transient receptor potential cation channels (TRPV1). FAAH inhibitors differ with respect to their potential for memory impairment, abuse liability, and probably other cannabis-like effects, and they should be evaluated individually for specific therapeutic and adverse effects.

Highlights

Cannabis and synthetic cannabinoid agonists can produce certain therapeutic effects, but they can produce adverse side effects including dependence and memory impairment
Testing of AM3506 in combination with antagonists for receptors known to be affected by anandamide and other fatty acid amides indicated that the impairment induced by AM3506 was mediated by cannabinoid CB1 receptors, and not by alpha-type peroxisome proliferator-activated receptors (PPAR-alpha) or vanilloid transient receptor potential cation channels (TRPV1)
We focused on the effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats, using a food-based procedure known to be sensitive to impairment by THC (Justinova et al 2013; Panlilio et al 2011, 2012)

Summary

Introduction

Cannabis and synthetic cannabinoid agonists can produce certain therapeutic effects, but they can produce adverse side effects including dependence and memory impairment. Since CB1 receptors have two separate endogenous ligands, it is likely that the brain circuits involving anandamide and 2-AG underlie distinct sets of neurobehavioral processes that can be selectively targeted for therapeutic purposes. This can be accomplished by administering inhibitors of FAAH or MGL, thereby increasing the effects of anandamide or 2-AG when and where they are released. This amplification of natural endocannabinoid signaling could potentially produce beneficial effects without the adverse side effects associated with exogenous cannabinoid agonists, which directly activate CB1 receptors throughout the brain (see reviews by Blankman and Cravatt 2013; Clapper et al 2009a; Hwang et al 2010; Panlilio et al 2013; Pertwee 2014; Schlosburg et al 2009; Zanettini et al 2011)

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