Abstract
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.