A Critical Role for the Cannabinoid CB₁ Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking

Abstract

Although many people drink alcohol regularly, only some become addicted. Several studies have shown that genetic and environmental factors contribute to individual differences in the vulnerability to the effects of alcohol (Nestler, 2000; Kreek, 2001; Crabbe, 2002). Among the environmental factors, stress is perhaps the most important trigger for relapse after a period of abstinence (Koob and Nestler, 1997; Piazza and Le Moal, 1998; Koob and Le Moal, 2001; Weiss et al., 2001). Here we show that ethanol withdrawal symptoms were completely absent in cannabinoid CB₁ receptor-deficient mice, although acute effects of ethanol and ethanol tolerance and preference were basically normal. Furthermore, foot-shock stress had no affect on alcohol preference in Cnr1^−/− mice, although it induced a dramatic increase in Cnr1^+/+ animals. These results reveal a critical role for the CB₁ receptor in clinically important aspects of alcohol dependence and provide a rationale for the use of CB₁ receptor antagonists in the treatment of alcohol addiction.