Date of Award

2026-05-01

Degree Name

Doctor of Philosophy

Department

Psychology

Advisor(s)

Laura E. O'Dell

Abstract

The rising prevalence of electronic cigarette (e-cigarette) use presents a major public health concern, particularly in adolescent females who are most susceptible to nicotine use and its long-term negative health consequences. The goal of this dissertation was to utilize preclinical rodent models to understand how group differences in age and sex influence neural activation patterns in brain circuits believed to promote nicotine withdrawal. Prior pre-clinical work, conducted largely in male rodents, has established that there are two major brain pathways that modulate the behavioral effects of nicotine withdrawal. These include the mesolimbic and medial habenula-interpeduncular nucleus (MHb-IPN) pathways. To assess the impact of age and sex on these neural circuits, we employed a statistical approach involving path analysis to determine the degree to which each of these factors impact withdrawal-induced neuronal activation in different brain regions within the aforementioned pathways. Adolescent/adult and female/male groups of rats were passively exposed to nicotine vapor plumes (12 mg/mL) or ambient air (controls) for 14 days in 90-minute sessions. After the final exposure session, all rats received an injection of the nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine (3.0 mg/kg) and physical signs of withdrawal and anxiety-like behavior were collected. We also quantified nosepokes in the port that delivered nicotine vapor on the first and last exposure session. Group differences in physical signs and approach behavior from my master's thesis have been published (Espinoza et al., 2022). Ninety minutes after mecamylamine administration, the rats were euthanized and brain sections containing our targeted brain regions were processed for Fos immunofluorescence or Nissl staining. A multi-group path analysis was employed to evaluate functional connectivity, with the MHb and lateral habenula (LHb) as exogenous predictors and the IPN, rostromedial tegmental nucleus (RMTg), ventral tegmental area (VTA), and nucleus accumbens (NAc) as endogenous outcomes. Our ANOVA analyses revealed the greatest activation in the terminal regions of the MHb-IPN and mesolimbic pathways. Specifically, the intermediate and rostral portions of the IPN displayed the largest withdrawal-induced activation in adolescent rats compared to adults. Additionally, the central portion of the IPN displayed the largest withdrawal-induced activation in female rats compared to males. Furthermore, while the NAc displayed greater withdrawal-induced activation in adolescent rats during withdrawal, this effect appeared to be driven by a lower baseline of Fos activation in adolescent controls. Multi-group analysis revealed that the mesolimbic pathway was significantly recruited in adolescent rats during withdrawal, but not adults. In contrast, the MHb-IPN pathway was not significantly recruited in any group during withdrawal. These findings identify age and sex differences in neural activation during withdrawal. This highlights potential clinical targets for reducing nicotine dependence in young populations.

Language

en

Provenance

Received from ProQuest

File Size

117 p.

File Format

application/pdf

Rights Holder

Veronika Espinoza

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