CB1‐Like Behavioral Effects of the Novel FAAH inhibitor AM3506

The enzyme that degrades the endocannabinoid anandamide (fatty acid amide hydrolase; FAAH) has been forwarded as a therapeutic target for metabolic and other disorders. The recently developed ligand, AM3506, inhibits FAAH selectively and with high potency (IC50: 2.8nM) and, as well, shows moderate CB1 receptor affinity (Ki: 192nM). The present work was conducted to study behavioral consequences of these actions by assessing the CB1‐like discriminative‐stimulus effects of AM3506 and, separately, those of anandamide (AEA) after treatment with AM3506 in squirrel monkeys (n=4) trained to discriminate 0.01 mg/kg of the THC‐like CB1 agonist AM4054. Results show that: a) a high dose of AM3506 (1.0 mg/kg) fully substituted for AM4054, whereas AEA failed to substitute over a wide dose range (1.0–32.0 mg/kg), presumably due to its rapid degradation; b) a 100‐fold lower dose of AM 3506 (0.01 mg/kg) sufficed to reveal CB1‐like effects of 5.6–10 mg/kg AEA; c) rimonabant served to antagonize the CB1‐like effects of AEA and AM3506 in a qualitatively dissimilar manner; d) based on Schild analysis, AM3506 (pA2=5.6) has CB1 receptor‐mediated actions that differ quantitatively from those of AM4054 (pA2=6.5). Together, these data indicate that CB1 receptor activation by AM3506 occurs at much higher doses than those that inhibit FAAH and may differ qualitatively from activation by conventional CB1 agonists. (Supported by NIH DA31020; DA19205)