Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol

Abstract

The aim of this study was to examine the role of fatty acid amide hydrolase (FAAH) on ethanol sensitivity, preference, and dependence. The deletion of FAAH gene or the inhibition of FAAH by carbamoyl‐biphenyl‐3‐yl‐cyclohexylcarbamate (URB597) (0.1 mg/kg) markedly increased the preference for ethanol. The study further reveals that URB597 specifically acts through FAAH and that cannabinoid‐1 (CB1) receptor is critical for N‐arachidonoyl ethanolamide (AEA) mediated ethanol‐reinforced behavior as revealed by lack of URB597 effect in both FAAH and CB1−/− mice compared with vehicle‐treated −/− mice. The FAAH −/− mice displayed a lower sensitivity to hypothermic and sedative effects to acute ethanol challenge. The FAAH −/− mice also exhibited a reduction in the severity of handling‐induced convulsions following withdrawal from chronic ethanol exposure. The CB1 receptor and proenkephalin gene expressions, and CB1 receptor and μ‐opioid (MO) receptor‐mediated G‐protein activation were found to be significantly lower in the caudate‐putamen, nucleus accumbens core and shell of FAAH −/− than +/+ mice. Interestingly, the MO receptor‐stimulated G‐protein signaling was greater in the striatum of FAAH −/− than +/+ mice following voluntary ethanol consumption. These findings suggest that an elevation in the AEA content and its action on the limbic CB1 receptor and MO receptor might contribute to ethanol‐reinforced behavior. Treatment with drugs that decrease AEA tone might prove useful in reducing excessive ethanol consumption.

Endocannabinoid system and drug addiction: new insights from mutant mice approaches

“…However, this acute paradigm fails to evaluate the maintenance of a stable operant self-administration responding, and the effects could be influenced by the stress induced by this restraint procedure. 15], in agreement with pharmacological results using CB 1 R antagonists [16]. Stress could participate in the regulation that CB 1 R exerts on alcohol consumption since stressinduced increase in ethanol preference is blocked in CB 1 KO [17].…”

“…These mutants exhibit more preference for ethanol intake [34,15], although another study found this enhancement only in female FAAHKO [35]. These inconsistencies may be due to differences in the genetic background.…”

“…These inconsistencies may be due to differences in the genetic background. Pharmacological studies showing that URB597 increases ethanol intake in mice [34,15] confirm that enhancing anandamide levels facilitates ethanol reward. In terms of ethanol withdrawal, FAAHKO display less intense handling-induced convulsions than control mice following withdrawal from chronic ethanol [15], although no differences were observed in an acute withdrawal paradigm [34].…”

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].…”

“…There are several studies which have attempted to investigate whether genetic or pharmacological manipulation of CB1 receptor function [54,55] and FAAH enzyme [56] could alter development of tolerance and dependence to alcohol. For instance, the CB1 receptor gene deleted mice (CB1-KO) mice, which are known to drink less alcohol, exhibit a greater sensitivity to alcohol [54].…”