Date of Award

Fall 2021

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Jill Turner

Abstract

Smoking remains the leading cause of morbidity and mortality in the United States, with less than 5% of smokers attempting to quit succeeding. This is due to the unpleasant withdrawal symptomology, which includes affective symptoms, such as irritability, weight gain, anxiety, and severe craving among others, as well as the cognitive effects, such as difficulty concentrating. This low smoking cessation success rate is also thought to be due to the long-lasting sensitization of nicotinic acetylcholine receptors (nAChRs) leading to long-term neuroadaptations in the brain’s reward system and alterations in synaptic plasticity that occur following chronic nicotine exposure and withdrawal. Glial cells, consisting of microglia, astrocytes, and oligodendrocytes, have recently emerged as active players in the development of dependence phenotypes. This is due to their roles in modulating neuronal functions and synaptic plasticity, both developmentally and postnatally [1-4], and increasing evidence indicates their role in drug dependence and its associated behavioral manifestations (see review [5]). There is also a role for neuroinflammation in drugs of abuse and the alterations of cytokines, small signaling proteins affecting cell signaling. Gaps remain in current literature as to the role of nicotine in altering the neuroimmune signaling within the brain’s mesocorticolimbic reward circuitry. In addition, it is unknown how if nicotine affects the reward pathway of males and females differently. Utilizing morphological analysis and biochemical techniques for mRNA and protein analysis, we analyzed the role of microglial cells as molecular driver of nicotine dependence and withdrawal-associated phenotypes. The sex differences found between males and females at the transcription and translational level within the various brain regions provide new insights to nicotine substance use disorder and may provide new pharmacological targets for future drug discovery.

Available for download on Friday, December 15, 2023

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