A growing body of evidence suggests that the endogenous cannabinoid system modulates the addictive properties of nicotine, the main component of tobacco that produces rewarding effects. In our study, complementary transgenic and pharmacological approaches were used to test the hypothesis that the endocannabinoid system modulates nicotine reward and dependence. An acute injection of nicotine elicited normal analgesic and hypothermic effects in cannabinoid receptor (CB) 1 knockout (KO) mice and mice treated with the CB 1 antagonist rimonabant. However, disruption of CB 1 receptor signaling blocked nicotine reward, as assessed in the conditioned place preference (CPP) paradigm. In contrast, genetic deletion, or pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for catabolism of the endocannabinoid anandamide, enhanced the expression of nicotine CPP. Although the expression of spontaneous nicotine withdrawal (14 days, 24 mg/ kg/day nicotine) was unaffected in CB 1 KO mice, acute administration of rimonabant (3 mg/kg) ameliorated somatic withdrawal signs in wild-type mice. Increasing endogenous levels of anandamide through genetic or pharmacological approaches exacerbated the physical somatic signs of spontaneous nicotine withdrawal in a milder withdrawal model (7 days, 24 mg/kg/day nicotine). Moreover, FAAH-compromised mice displayed increased conditioned place aversion in a mecamylamine-precipitated model of nicotine withdrawal. These findings indicate that endocannabinoids play a role in the rewarding properties of nicotine as well as nicotine dependence liability. Specifically, increasing endogenous cannabinoid levels magnifies, although disrupting CB 1 receptor signaling, attenuates nicotine reward and withdrawal. Taken together, these results support the hypothesis that cannabinoid receptor antagonists may offer therapeutic advantages to treat tobacco dependence.Nicotine is the main addictive component in tobacco that acts on the brain to produce rewarding effects and aversive events upon cessation. When neuronal nicotinic acetylcholine receptors (nAChRs) are activated by nicotine, several neurotransmitters are released (i.e., dopamine, norepinephrine, serotonin, and GABA), activating multiple neuronal systems that may regulate nicotine addiction (Wonnacott et al., 1989(Wonnacott et al., , 2005Castañ é et al., 2005). The endocannabinoid system has been implicated in addictive behavior and in the mechanism of action of several drugs of dependence, including nicotine. This system contains cannabinoid receptors (CB 1 and CB 2 ), the endocannabinoids anandamide (AEA) and 2-arachidonoyl-glycerol, and the enzymes involved in their synthesis and metabolism, for example, anandamide-e [i.e., fatty acid amide hydrolase (FAAH)] and 2-arachidonoyl-glycerol (i.e., monoacylglycerol lipase) (Rodríguez de Fonseca et al., 2005). Furthermore, reports have shown that AEA binds with highest affinity to CB 1 receptors on presynaptic neurons and activates the mesolimbic reward pathway, t...