Developmental Impacts of Adolescent Intermittent Nicotine Vapor Exposure on the Murine Hippocampus

Abstract ID 92515 Poster Board 119 Electronic cigarette (e-cig) use is rapidly rising, especially among adolescents and younger adults. Despite their development as a smoking cessation aid, young adult (18-24 yo) e-cig users are generally also "never smokers" (less than or equal to 100-lifetime cigarettes consumed), suggesting that many new nicotine users are initiating use with e-cigs. This trend is troubling, as nicotine dependence during adolescence is associated with numerous health-related outcomes later in life, including a higher risk for psychiatric disorders. Adolescence represents a period of dynamic brain development, particularly in the prefrontal cortex and limbic regions. One limbic region of particular interest is the hippocampus, which directly contributes to both cognitive and affective nicotine withdrawal symptoms, and its maturation during adolescence is significantly impacted by nicotine exposure. However, mechanistic understanding of this process and how to leverage this knowledge for treatment is unknown. In order to investigate the developmental impacts of chronic nicotine exposure, we first used the La Jolla Research, Inc. nicotine vapor chambers to expose adult (9-week) C57BL6 mice to intermittent nicotine via inhalation. Mice had food and water available ad libitum and were maintained on a 12-hour light-dark cycle (lights on at 7:00 AM). We exposed mice during the dark phase and varied puff duration, number of puffs a cycle, and time between cycles to produce concentrations of plasma cotinine comparable to heavy human smokers and the canonical nAChR upregulation seen in both human smokers and rodents exposed to chronic nicotine. This novel method provides a non-invasive nicotine exposure model, produces nicotine inhalation topography that more closely matches human users, and only exposes mice to nicotine during their active phase. Using this newly developed exposure model, we treated adult (9-week) and adolescent (5-week) C57BL6 mice to two weeks of nicotine exposure, followed by 2 weeks of abstinence. On the 14th day of abstinence, mice were sacrificed, and hippocampal samples were taken for RNA-sequencing. Preliminary cell-type-specific RNA-sequencing data from adult exposed mice suggests that during acute nicotine withdrawal, immune signaling pathways are disrupted. However, at the prolonged withdrawal time point of two weeks, the adolescent nicotine-exposed mice have unique changes in their neuronal transcriptome not present in the adult-exposed mice. Further validation of the developmental impacts of nicotine on the hippocampal neuronal transcriptome is ongoing, and possible proteomic changes will be investigated in validated genes of interest. NIH/NIDA grant DA044311 University of Kentucky Substance Use Priority Research Area (SUPRA) Equipment Grant University of Kentucky Substance Use Priority Research Area (SUPRA) Faculty Pilot Grant American Foundation for Pharmaceutical Education Predoctoral Fellowship