Inhibition of endocannabinoid‐inactivating enzymes and cannabinoid (CB1) discrimination (838.1)

The discriminative‐stimulus (S d ) and other behavioral effects of CB1 ligands can be reproduced in mice by combined inhibition of the anandamide‐ (AEA‐) and 2‐arachidinoyl glycerol‐ (2‐AG‐) inactivating enzymes fatty‐acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL; Long et al. 2009). The present studies using selective and non‐selective ligands [FAAH (URB 597;AM 2018), MGL (AM 2036); mixed (AM 2129), and FAAH /CB1 (AM 3506) were conducted to further explore effects of mixed FAAH and MGL inhibition in squirrel monkeys that discriminate CB1 agonists (AM 4054;THC) from vehicle (n=4). Results indicate that: 1) mixed (but not FAAH‐ or MGL‐selective) inhibition or the combination of FAAH inhibition with some CB1 activity reproduced CB1‐related S d effects, and 2) anandamide produced these effects after treatment with relatively low doses of non‐selective and FAAH‐selective enzyme inhibitors. Schild analysis of data from antagonism studies suggest some differences in the interaction of the several types of agonist effect with the CB1 receptor. The present data strengthen the idea that complementary, but not individual, actions of the endocannabinoids AEA and 2‐AG produce CB1‐related S d , and perhaps subjective, effects in primate species. Grant Funding Source : Supported by NIH/NIDA RO1‐31020