UC Irvine

Nicotine, the main psychoactive constituent in tobacco, is highly addictive and poses a particular vulnerability to adolescents. Adolescence is a critical period of neurodevelopment when nicotine use is initiated. Nicotine is the exogenous ligand for nicotinic acetylcholine receptors (nAChRs). The alpha()6 nAChR subunit (encoded by the CHRNA6 gene) reaches peak expression in dopaminergic neurons of the midbrain during adolescence. A ‘C’ to ‘G’ single nucleotide polymorphism (SNP) in the 3’-untranslated region (UTR) of the CHRNA6 gene (rs2304297) has been associated with nicotine addiction in adolescent humans. Discerning the genetic and neurobiological mechanisms impacting adolescent nicotine seeking could help with improved prevention and intervention strategies in humans. My findings illustrate that nicotine-seeking behavior could be assessed in adolescent wild type male and female Sprague Dawley rats using a self-administration and reinstatement paradigm, a model of relapse behavior in humans. Further, I show that the CHRNA6 3’-UTR SNP elicits sex- and genotype-dependent nicotine seeking behavior, with 6GG male adolescents most vulnerable. Mechanistically, I illustrate that dopaminergic mechanisms underlie deficits in nicotine seeking behavior, Taken together, the results of the present study will add to a growing body of literature that the CHRNA6 3’-UTR SNP sex- and genotype-dependently contribute to adolescent nicotine addiction with dopaminergic circuits involved.