Evaluation of FAAH‐ and MGL‐Inhibition in Cannabinoid Drug Discrimination

Abstract

The discriminative‐stimulus (SD) effects of CB1 ligands can be reproduced in mice by non‐selective inhibition of the anandamide‐(AEA‐) and 2‐arachidinoyl glycerol‐(2‐AG‐) inactivating enzymes, respectively, fatty‐acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGL). Additionally, we have shown that nonselective FAAH/MGL inhibitors produce a CB1‐like SD effect in squirrel monkeys. The present studies with selective and nonselective ligands [FAAH (URB597; AM2018), MGL (AM2036); and FAAH/MGL‐mixed (AM2129)] were conducted to further evaluate the effects of FAAH and MGL inhibition in squirrel monkeys trained to discriminate the CB1 agonist AM4054 from vehicle (n=4). Results indicate that: 1) co‐administration of selective FAAH‐ and MGL‐inhibitors, but not FAAH‐ or MGL‐selective inhibitors alone, produces CB1‐related SD effects;2) AEA, but not 2‐AG, produces CB1‐like SD effects after either FAAH or mixed FAAH/MGL inhibition; and 3) CB1 receptor antagonism effectively and blocks the CB1‐like effects of combined FAAH/MGL inhibition; this effect was insurmountable. The present data strengthen the idea that complementary, but not individual, actions of the endocannabinoids AEA and 2‐AG produce CB1‐related SD, and perhaps subjective, effects in primate species.