Date of Award

Summer 2019

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Jill Turner

Abstract

Neurons are the primary research target in the exploration and development of novel smoking cessation pharmacotherapies over the years. These research efforts have led to the discovery and development of three FDA-approved smoking cessation aids – nicotine replacement therapy, varenicline, and bupropion, each of which have quantifiable success as smoking cessation aids. However, relapse is still very common and smoking cessation is successful in less than 5% of quit attempts, making paramount the development of novel therapeutics. One untapped therapeutic target are glia, particularly, astrocytes and microglia, which are active participants in the neuroplastic events underlying drug addiction.

First, we examined microglial changes in the striatum – a mesolimbic brain region implicated in both the rewarding effects of drugs and the affective disruptions occurring during drug withdrawal. We show that chronic nicotine and withdrawal induce microglial activation accompanied with distinct expression of pro-inflammatory cytokines in the nucleus accumbens. Nicotine withdrawalrelated pro-inflammatory effects accompany activation of microglia-related NADPH Oxidase 2 (Nox2) and induction of reactive oxygen species (ROS). Both cellular correlates of inflammation and increased anxiety-like behaviors occurring during nicotine withdrawal are absent following microglial depletion with colony stimulating factor 1 receptor inhibitor, PLX5622.

Based on these findings, we extended our study to capture tissue-level transcriptome-wide responses in the nucleus accumbens during chronic nicotine and withdrawal (24 h and 48 h). We show temporally-dependent activation of distinct gene programs in the nucleus accumbens during nicotine withdrawal. Differential gene expression analysis suggests that chronic nicotine treatment activates subset of genes that are neuroprotective while withdrawal from nicotine provokes neuroinflammation and oxidative stress-related transcriptional programs in the nucleus accumbens

To have a finer resolution that aid better characterization of transcriptomic changes, we performed cell type-specific RNA sequencing and evaluated astrocyte- and microglia-specific transcriptome changes during nicotine treatment and 48 h withdrawal. We show that gene programs associated with neuroinflammation were suppressed in microglia following chronic nicotine treatment while nicotine withdrawal triggers microglial pro-inflammatory networks. Further, whole transcriptome data suggest astrocytes assume a reactive phenotype during nicotine withdrawal.

Taken together, this work provides the first evidence of microglia involvement in nicotine dependence. In addition, our transcriptomic studies offer a less complex insight into the role of nucleus accumbal glia in nicotine dependency, pioneering future exploration of glia modulators as potential therapeutic targets for the development of smoking cessation therapeutics.

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