Involvement of Endocannabinoids in Alcohol "Binge" Drinking: Studies of Mice with Human Fatty Acid Amide Hydrolase Genetic Variation and After CB1 Receptor Antagonists

Background The endocannabinoid system has been found to play an important role in modulating alcohol intake. Inhibition or genetic deletion of fatty acid amide hydrolase (FAAH; a key catabolic enzyme for endocannabinoids) leads to increased alcohol consumption and preference in rodent models. A common human single‐nucleotide polymorphism (SNP; C385A, rs324420) in the FAAH gene is associated with decreased enzymatic activity of FAAH, resulting in increased anandamide levels in both humans and FAAH C385A knock‐in mice. Methods As this FAAH SNP has been reported to be associated with altered alcohol abuse, the present study used these genetic knock‐in mice containing the human SNP C385A to determine the impact of variant FAAH gene on alcohol “binge” drinking in the drinking‐in‐the‐dark (DID) model. Results We found that the FAAHA/A mice had greater alcohol intake and preference than the wild‐type FAAHC/C mice, suggesting that increased endocannabinoid signaling in FAAHA/A mice led to increased alcohol “binge” consumption. The specificity on alcohol vulnerability was suggested by the lack of any FAAH genotype difference on sucrose or saccharin intake. Using the “binge” DID model, we confirmed that selective CB1 receptor antagonist AM251 reduced alcohol intake in the wild‐type mice. Conclusions These data suggest that there is direct and selective involvement of the human FAAH C385A SNP and CB1 receptors in alcohol “binge” drinking. Genotypic difference in alcohol intake in 4‐day drinking‐in‐the‐dark model (A) and alcohol preference on day 5 (B) in FAAH knock‐in mice: alcohol intake was recorded at 4‐h time point for 4 consecutive days in FAAHA/A, FAAHC/A, and FAAHC/C mice; the mice were then tested on day 5 for alcohol vs. water preference. FAAHA/A mice showed greater alcohol intake and preference than wild‐type FAAHC/C mice, suggesting that increased endocannabinoid signaling in FAAHA/A mice led to increased alcohol “binge” consumption.