Adolescence is an important period in development where brain maturation is uniquely vulnerable to nicotine. Approximately one in three high school-aged students currently use tobacco/nicotine-containing products in the United States. Epidemiological and preclinical studies suggest that adolescent nicotine exposure results in long-lasting effects including nicotine dependence and progression to illegal substance use. Nicotine is the exogenous ligand for nicotinic acetylcholine receptors (nAChRs). Alpha(α)6 nAChR subunits reach peak expression in the dopaminergic neurons of the midbrain during adolescence, when initiation and establishment of tobacco/nicotine-containing product use usually occurs. Furthermore, a C to G single nucleotide polymorphism (SNP), rs2304297, in the 3’-untranslated region (UTR) of the α6 nicotinic receptor subunit gene, CHRNA6, has been associated with nicotine dependence and substance use. With the popularity of e-cigarette use among adolescents, it is essential to identify mechanisms underlying the health consequences of developmental nicotine exposure.I explore the effects of nicotine on subsequent opioid and stimulant self-administration using a low-dose, 4-day nicotine pretreatment paradigm in adolescent and adult male and female rats. To explore the role of α6-containing (α6*, denotes nicotinic receptors with the α6 subunit) nAChRs in nicotine-induced behaviors, I characterize a novel humanized CHRNA6 3’-UTR mutant rat line in which the 3’-UTR of the CHRNA6 gene in the rat was replaced with the human 3’-UTR containing the SNP alleles (C or G) associated with nicotine behaviors. To evaluate the role of the CHRNA6 3’-UTR SNP in adolescent substance use, I assessed the role of the CHRNA6 3’-UTR SNP in nicotine-induced mRNA expression, locomotor activity, anxiety-like behavior, and methamphetamine (METH) self-administration. I additionally investigated the role of α6* nAChRs in nicotine-induced METH self-administration via a targeted knock down approach.
Taken together, findings show that adolescent, but not adult, nicotine exposure enhances subsequent cocaine, fentanyl, and METH self-administration. In the humanized CHRNA6 3’-UTR mutant line, I show that the human SNP is functional in vivo and that there are no alterations in behaviors that have been shown not to be impacted by α6* nAChRs; however, there are bidirectional sex-dependent nicotine-induced behavioral effects. Finally, I show that α6 nAChR subunit knockdown impacts adolescent nicotine-induced methamphetamine self-administration behavior. Overall, the dissertation emphasizes the complexity of risk factors that impact the behavioral effects of nicotine, including timing of exposure, sex, and genetics, and highlights potential molecular therapeutic targets.