Role of Endocannabinoids in Alcohol Consumption and Intoxication: Studies of Mice Lacking Fatty Acid Amide Hydrolase

Abstract

Endocannabinoid signaling plays the important role in regulation of ethanol intake. Fatty acid amide hydrolase (FAAH) is a key membrane protein for metabolism of endocannabinoids, including anandamide, and blockade of FAAH increases the level of anandamide in the brain. To determine if FAAH regulates ethanol consumption, we studied mutant mice with deletion of the FAAH gene. Null mutant mice showed higher preference for alcohol and voluntarily consumed more alcohol than wild-type littermates. There was no significant difference in consumption of sweet or bitter solutions. To determine the specificity of FAAH for ethanol intake, we studied additional ethanol-related behaviors. There were no differences between null mutant and wild-type mice in severity of ethanol-induced acute withdrawal, conditioned taste aversion to alcohol, conditioned place preference, or sensitivity to hypnotic effect of ethanol. However, null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol. All three behavioral phenotypes (increased preference for ethanol, decreased sensitivity to ethanol-induced sedation, and faster recovery from ethanol-induced motor incoordination) seen in mutant mice were reproduced in wild-type mice by injection of a specific inhibitor of FAAH activityFURB597. These data suggest that increased endocannabinoid signaling increased ethanol consumption owing to decreased acute ethanol intoxication.

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

“…In our experiments, URB597 was injected peripherally at doses that can inhibit FAAH activity in the whole brain (Kathuria et al 2003). Several major methodological differences can be also identified between our study and the report published by Blednov et al (2007). For example, our experiments used Wistar rats operantly self-administering alcohol or msP rats taking alcohol under limited access conditions.…”

“…The same study showed that intra-prefrontal cortex administration of URB597 increased operant alcohol self-administration in nonselected Wistars. More important, Blednov et al (2007) reported that FAAH knockout mice voluntarily consume more alcohol than wild-type littermates, while treatment with URB597 increases alcohol intake in wildtype mice. In contrast with these earlier findings, in the present study, alcohol intake was not affected by URB597 administration.…”

Endocannabinoid system involvement in brain reward processes related to drug abuse

“…Such studies have confirmed that the rewarding effects of ethanol require CB1 receptor activation since CB1 knock out mice do not develop preferences for ethanol-paired compartments (144,159). In addition, pharmacological blockade or genetic ablation of FAAH enzymes in mice increase ethanol preference and intake in a two-bottle free-choice procedure (166,167). The prefrontal cortex and the nucleus accumbens appear two brain regions implicated in the modulation of the reinforcing effects of ethanol by cannabinoids (168,169).…”

Role of the Endocannabinoid System in Alcohol-Related Behaviors

“…The severity of HIC is found to be lower in FAAH-KO than WT mice [56]. Conversely, Blednov et al, (2007) reported no difference in the HIC in these mice [64]. The possible explanation for this inconsistency might be due to differences in alcohol dosage administered (chronic versus acute).…”

“…There are a limited number of studies that have investigated the role of FAAH in alcohol drinking behavior [55,64,92]. It was reported that the mice lacking FAAH gene on a mixed genetic background (B6/129SV/J) consume significantly more alcohol compared to their WT counterparts [92].…”