Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB 1 receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB 1 receptor significantly reduced the ethanol preference. Although the stimulation of the CB 1 receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB 1 receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB 1 -/-mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB 1 receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB 1 receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB 1 receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB 1 receptor may have therapeutic potential in the treatment of ethanol dependence.