Sex- and Genotype-Dependent Nicotine-Induced Behaviors in Adult Rats with a Human Polymorphism (rs2304297) in the 3’-UTR of the CHRNA6 Gene

Introduction The widespread use of nicotine across ages culminates in substantial consequences on individual health, public health, and broader socioeconomic strain. Concerningly, adolescence is a uniquely vulnerable stage in which exploratory drug exposure imposes detrimental effects on reward circuitry, cognitive function, and neurochemical processes. A single nucleotide polymorphism (SNP), rs2304297, in the 3’-untranslated region (UTR) of the CHRNA6 gene has been linked to increased nicotine use in humans. To investigate the impact of this SNP, we engineered a humanized rat line and have demonstrated sex and genotype dependent effects on nicotine-induced behaviors in adolescent rats. Prior work identified neurochemical differences in the nucleus accumbens in both drug-naïve and nicotine treated humanized adolescent rats. Methods In this study, we aim to determine how four days of nicotine pretreatment (2 x 30 μg/kg nicotine, i.v.) impacts behavior and dopamine-related protein expression in the critical ventral tegmental area and nucleus accumbens in female and male adolescent and adult human CHRNA6 3’-UTR SNP rats. Results We show that nicotine enhances locomotor activity in adolescent female α6CC rats and male α6GG rats, while only enhancing locomotor activity in adult female α6CC rats. We found higher tyrosine hydroxylase (dopamine synthesis marker) levels in the ventral tegmental area of adolescent male α6GG rats compared to male α6CC rats independent of drug exposure. Conclusions These findings demonstrate age differences in the sex and genotype dependent effects of the human CHRNA6 3’-UTR SNP in nicotine-induced behavior and provide novel evidence for genotype dependent differences in protein expression. Implications The present study highlights novel genetic influences on nicotine-induced behavior that have unique age and sex differences.