Mutation of the α5 Nicotinic Acetylcholine Receptor Subunit Increases Ethanol and Nicotine Consumption in Adolescence and Impacts Adult Drug Consumption

Alcohol and nicotine are commonly used during adolescence, establishing long-lasting neuroplastic alterations that influence subsequent drug use and abuse. Drinking- and smoking-related traits have been extensively associated with variation in CHRNA5 - the gene that encodes the α5 subunit of neuronal nicotinic acetylcholine receptors (nAChRs). The single nucleotide polymorphism (SNP) rs16969968 in CHRNA5 encodes an amino acid substitution (D398N) that alters the function and pharmacokinetics of α5-containing nAChR. When expressed in rodents, this variant results in increased ethanol and nicotine operant self-administration. How disruption of α5-containing nAChRs influences adolescent ethanol and nicotine intake, and how it modulates interactions between these drugs has not been previously explored. In the present study, we examined volitional ethanol and nicotine consumption in adolescent mice (post-natal day 30-43) of both sexes with mutated (SNP) or lacking (KO) the α5 nAChR subunit. The effect of adolescent alcohol or nicotine exposure on home cage consumption of the opposite drug in adulthood and its modulation by Chrna5 mutation and sex were examined. During adolescence, we found that α5 nAChR disruption increases nicotine intake in mice of both sexes, but the effect on alcohol intake was only observed in females. The sex-specific increase in alcohol consumption in α5 SNP and KO was replicated in adulthood. The effect of adolescent alcohol or nicotine exposure on subsequent intake of the opposite drug in adulthood is modulated by sex and Chrna5 mutation. These observations suggest sex differences in the genetic architecture of alcohol dependence, and modulators of alcohol and nicotine interactions.