Sub-chronic nicotine exposure influences methamphetamine self-administration and dopamine overflow in a sex-and genotype-dependent manner in humanized 6 3'-UTR SNP (rs2304297) adolescent rats.

The rewarding effects of drugs of abuse are associated with the dopaminergic system in the limbic circuitry. Nicotine exposure during adolescence is linked to increased use of drugs of abuse with nicotine and methamphetamine (METH) commonly used together. Nicotine acts on neuronal nicotinic acetylcholine receptor (nAChR) systems, critical for reward processing and drug reinforcement, while METH leads to a higher dopamine (DA) efflux in brain reward regions. A human single nucleotide polymorphism (SNP) in the 3'-untranslated region (UTR) of the α6 nicotinic receptor subunit gene (6, rs2304297), has been linked with tobacco/nicotine and general substance use during adolescence. Using CRISPR-Cas9 genomic engineering, our lab recapitulated the 6 3'UTR SNP, generating α6 and α6 allele carriers in Sprague Dawley rats. We hypothesized the 6 3'UTR SNP would sex- and genotype-dependently enhance nicotine-induced METH self-administration as well as nicotine-induced DA overflow in the nucleus accumbens shell of adolescent α6 and α6 carriers. Adolescent male and female rats underwent a 4-day sub-chronic, low-dose (0.03 mg/kg/0.1 mL, x2) nicotine pretreatment paradigm to assess intravenous METH (0.02 mg/kg/0.1 mL) self-administration as well as nicotine- and METH (0.02 mg/kg/0.1 mL)-induced DA overflow in the nucleus accumbens shell (NAcS) using microdialysis coupled with high-performance liquid-chromatography-electrochemical detection (HPLC-ECD). Nicotine pretreatment sex- and genotype-dependently enhanced subsequent METH self-administration in adolescent 6 3'UTR SNP rats. Further nicotine and METH-induced DA overflow is observed in α6 females as compared to α6 females, with METH-induced DA overflow enhanced in α6 males when compared to α6 males. These findings demonstrate that the 6 3'-UTR SNP can sex- and genotype-dependently impact adolescent nicotine-induced effects on METH self-administration and stimulant-induced DA overflow in reward regions of the brain.