Smoking-Related Increases in Alcohol Outcomes and Preliminary Evidence for the Protective Effect of a Functional Nicotine Receptor Gene (CHRNA5) Variant on Alcohol Consumption in Individuals Without Alcohol Use Disorder.

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Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and misuse of these drugs. A missense polymorphism rs16969968 (G>A) in the CHRNA5 gene has shown a strong association with nicotine-related phenotypes. However, less is known about the impact of this variant on alcohol-related phenotypes. We assessed the main and interactive effect of smoking and rs16969968 polymorphism on alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT), Timeline Follow Back (TLFB), and Lifetime Drinking History (LDH) in 980 healthy adults without alcohol use disorder. We further examined the effect of the rs16969968 polymorphism on acute alcohol consumption using a free-access i.v. alcohol self-administration (IV-ASA) human laboratory paradigm in a subset of 153 nonsmoking participants. Subjective alcohol responses, alcohol sensitivity, and expectancy measures were compared between genotype groups (GG; AA/AG). We observed a significant association of smoking with AUDIT, TLFB, and LDH measures across genotype groups, with smokers showing higher scores compared with nonsmokers. Additionally, we found an association between genotype and TLFB-total drinks in the IV-ASA subset, with the GG group showing higher scores than AA/AG group. Relatedly, the alcohol negative expectancy score was significantly lower in the GG group than the AA/AG group. Our findings underscore the association of smoking with alcohol measures. We found preliminary evidence for the protective effect of the functional CHRNA5 polymorphism on alcohol consumption and its association with increased negative alcohol expectancies, which highlights the substantial heterogeneity in alcohol responses.