Deletion or enhancement of alpha-2 nAChRs (Chrna2) induces unique lifespan behavioral deficits

Exposure to nicotine is known to have unique lifespan effects, with sexual dimorphisms suggested to exist in learning and memory during both adolescence and adulthood. Using a fear conditioning paradigm, we assessed whether genetic manipulation of the Chrna2 gene (Chrna2^-/- or Chrna2^+/+) resulted in alterations to learning and memory in adolescent female and male mice and female adult mice. We also assessed whether hyperexcitability of the Chrna2 gene (Chrna2^L9'S/L9'S) in male adult mice would result in differences in nicotine but not food reinforcement as compared with Chrna2^+/+ (wild-type) mice. We found that adolescent and adult female Chrna2^-/- mice demonstrated no significant differences in learning and memory behavior, while adult male Chrna2^-/- mice demonstrated deficits in learning and memory behavior. Given that our prior studies found that male adolescent Chrna2^-/- mice had deficits in learning and memory behavior, we then examined female adolescent Chrna2^-/- mice and found they extinguished independent of drug treatment during extinction testing. In contrast, female adult nicotine-exposed Chrna2^-/- mice did not have decreased freezing but increased in freezing behavior during extinction testing. Independent of nicotine pre-treatment, male Chrna2^+/+ adolescents, but not Chrna2^-/-, mice had decreased freezing behavior during extinction testing while these effects were absent in adults. Hypersensitivity of Chrna2 in adult mice also resulted in diminished acquisition of nicotine self-administration as compared with Chrna2^+/+ male mice and a significantly decreased nicotine infusion at 0.1 mg/kg as compared with wild-type animals, with no impact on food reinforcement. Our study overall suggests that ∝2-containing nAChRs play age- and sex-dependent roles in nicotine modulated behaviors.