Genetic Impairment of Frontocortical Endocannabinoid Degradation and High Alcohol Preference

Abstract

Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoidrelated genes in key brain regions of reward and dependence, and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines. A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats, and was accompanied by decreased enzyme activity in this region. Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand 3 [H]SR141716A, and [35S]GTPgS incorporation stimulated by the CB1 agonist WIN 55,212-2 were downregulated in the same area. Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals, and a compensatory downregulation of CB1 signaling. The functional role of impaired FAAH function for alcohol self-administration was validated in two independent ways. The CB1 antagonist SR141716A potently and dose-dependently suppressed self-administration in AA rats when given systemically, or locally into the PFC, but not in the striatum. Conversely, intra-PFC injections of the competitive FAAH inhibitor URB597 increased ethanol self-administration in nonselected Wistar rats. These results show for the first time that impaired FAAH function may confer a phenotype of high voluntary alcohol intake, and point to a FAAH both as a potential susceptibility factor and a therapeutic target.

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

“…In a recent report, Vinod et al (2006) reported reduction in FAAH activity and increased cortical levels of anandamide in mice exposed to alcohol vapour for 72 h. Moreover, Hansson et al (2007) found reduced FAAH expression and activity in the prefrontal cortex of Finnish alcohol-preferring AA rats when compared with ANA. The same study showed that intra-prefrontal cortex administration of URB597 increased operant alcohol self-administration in nonselected Wistars.…”

“…At present, the reasons for the discrepancy between the results of the present work and the previous studies are unclear, though it is possible that several methodological factors may be involved. For example, Hansson et al (2007) microinjected the compound directly into the prefrontal cortex, thus selectively increasing endocannabinoid activity in this nucleus. In our experiments, URB597 was injected peripherally at doses that can inhibit FAAH activity in the whole brain (Kathuria et al 2003).…”

Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans

“…Recently, it was reported that endocannabinoid transmission was increased and Cnr1 expression was decreased as feedback in the prefrontal cortex of alcoholpreferring rats. 28 Taken together, these findings suggests that high endocannabinoids activity, which is stimulated by stress, appears to be related to alcohol preference, which induces a compensatory downregulation of Cnr2 in brain. It is possible that endocannabinoids act like endorphin for reward in the brain and that high Cnr2 signal in brain may be a key modulator of susceptibility to alcoholism under condition of stress.…”

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

“…These results show that cannabinoid receptor agonists and antagonists stimulate and suppress, respectively, alcohol intake, alcohol selfadministration, and alcohol's motivational properties (see Colombo et al (2005) and, Maldonado et al (2006) for review). Hansson et al (2006) demonstrated a decrease of FAAH expression and activity in prefrontal cortex of alcohol-preferring AA rats compare with nonpreferring ANA rats. They also showed that elevated endocannabinoid transmission in brain of AA animals was accompanied by a compensatory downregulation of CB1 signaling.…”