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There is growing recognition that cannabinoid receptor type 1 (CB1) plays a major role in alcohol and other drug addictions.1–6 Much of this work has focused on the interaction between the cannabinoid system and neuronal substrates that underlie drug-seeking behavior (Kalivas and Volkow7 provide a review of the neurobiologic mechanisms). The CB1 receptor is the most prevalent G protein–coupled receptor in the brain, and the CB1 receptor is densely localized to the same structures that underlie drug-seeking behavior (eg, the ventral tegmental area [VTA], nucleus accumbens [NAcc], prefrontal cortex [PFC], basolateral amygdala, and hippocampus). On a mechanistic level, the cannabinoid system regulates the release of dopamine, γ-aminobutyric acid (GABA), and glutamate. The CB1 receptors located on GABA interneurons suppress GABA release, which disinhibits dopaminergic projections to the accumbens and increases dopaminergic activation (Maldonado et al5 and De Vries and Schoffelmeer6 provide reviews). The CB1 receptors also regulate glutamatergic projections from the basolateral amygdala and hippocampus by inhibiting the release ofGABA and GABAergic projections from the accumbens to the VTA, indirectly activating the VTA.5,6 With respect to alcohol, the CB1 receptor mediates the effects of alcohol on the neuronal circuitry that underlies reward and the attribution of incentive salience. Recent studies have demonstrated that CB1 antagonists (eg, rimonabant) block the ability of alcohol to initiate the release of dopamine in the accumbens,3 decrease alcohol intake in alcohol- preferring8–12 and normal13 rats, and prevent the ability of cues associated with alcohol and other drugs to reinstate consumption. 6,14–16 In addition, CB1 agonists increase alcohol intake in rats.17 Moreover, CB1 knockout mice consume less alcohol, 3,18–20 show deficits in cue-initiated reinstatement and place preference,20,21 and do not demonstrate alcohol withdrawal symptoms22 or alcohol-induced increases in dopamine release in the accumbens. 3,19 Furthermore, alcohol-preferring animals have greater levels of CB1 messenger RNA in the structures that underlie drug-seeking behavior.23 Thus, the evidence is clear about the importance of the CB1 receptor and the gene that codes for this receptor (CNR1 [OMIM 114610]).3 Despite findings from the animal literature, similar studies in the human literature are almost nonexistent. Although a CB1 antagonist has been tested with nicotine dependence, to our knowledge, there have been no published trials with alcohol dependence. Regarding the gene that codes for the CB1 receptor, several studies24–26 found an association between CNR1 genetic variants and alcohol dependence, and 2 others27,28 did not. Contradictory results are not surprising given the many variables that affect the development of alcohol dependence, the potential error in the assignment of the diagnosis, and the dichotomous nature of a variable that reflects a spectrum disorder. Thus, the use of alcohol dependence as the sole phenotypic end point is a limitation. One of these studies25 noted that several single-nucleotide polymorphisms (SNPs) were associated with messenger RNA changes, and these same SNPs also overlap with SNPs associated with a reward-related neuroimaging phenotype.29 The present investigation encompassed multiple approaches, including receptor binding in postmortem brain tissue, functional magnetic resonance imaging, human laboratory models, and analyses of treatment outcome data. Specifically, this investigation was designed to test the effect of a specific CNR1 SNP (rs2023239) associated with substance dependence and CNR1 messenger RNA changes25 and linked to loci associated with a neuroimaging phenotype. 29 Three hypotheses were tested: (1) rs2023239 may be associated with differential CB1 binding in the PFC based on previous evidence suggesting a link with messenger RNA levels25; (2) rs2023239 may be associated with differences in brain activation during the presentation of alcohol cues using a neuroimaging paradigm and may be associated with the rewarding effects of alcohol based on previous evidence suggesting an association with neuroimaging phenotypes and the extensive literature on the importance of the CB1 receptor in alcohol reward; and (3) rs2023239 may be associated with the effects of a medication on the incentive salience of alcohol and drinking behavior in a treatment outcome trial based on the notion that the medication is effective because it dampens mesocorticolimbic activity.

Context Given the probable importance of the α4 subunit of the neuronal nicotinic acetylcholine receptor, the gene that codes for this subunit ( CHRNA4 ) represents an excellent starting point for a genetic investigation of smoking behavior. Objective To achieve a better understanding of the role of this gene in the cause and treatment of tobacco dependence, we adopted a transdisciplinary pharmacogenetic approach. Design Study at the behavioral and clinical levels of analysis. Setting Academic research. Participants Smokers (n = 316) between the ages of 18 and 50 years were recruited from the Denver, Colorado, metropolitan area. Main Outcome Measures Bioinformatics analyses, cell culture experiments, and analyses of CHRNA4 expression and nicotine binding in postmortem human brain tissue advanced 2 single-nucleotide polymorphisms ( rs6122429 and rs2236196 ). Results Both single-nucleotide polymorphisms were associated with subjective responses to smoking in the laboratory among 316 smokers. Likewise, among 353 participants in a clinical trial, rs2236196 was associated with smoking cessation outcomes. Conclusions Results of analyses ranging from basic biological approaches to clinical outcome data provide consistent evidence that 2 single-nucleotide polymorphisms in CHRNA4 are functional at a biological level and are associated with nicotine dependence phenotypes. This interdisciplinary approach to the genetics of nicotine dependence provides a model for testing how functional genetic variation is translated from changes in messenger RNA and protein to individual differences in behavior and treatment outcome.