1. ¹Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA
2. ²Fundation IMABIS, Malaga, Spain
3. ³National Public Health Institute, Helsinki, Finland
4. ⁴Department of Pharmacology, University of Bologna, Bologna, Italy
5. ⁵Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
6. ⁶Laboratory of Neuroendocrinology, NIAAA, Bethesda, MD, USA

Correspondence: Dr M Heilig, Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Building 10, CRC, E1-5334, 10 Center Dr MSC 1108, Bethesda, MD 20892-1108, USA. Tel: +1 301 4359386; Fax: +1 301 402 0445; E-mail: markus.heilig@mail.nih.gov

⁷These authors contributed equally to this study.

Received 31 August 2005; Revised 2 December 2005; Accepted 8 December 2005; Published online 8 February 2006.

Abstract

Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoid-related 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]GTPS 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.