Microglial Modulation of Nicotine Dependence

点击翻译按钮获取中文摘要

Project Summary/Abstract: Notwithstanding great strides in lowering the percentage of smoking adults, close to a billion people a year continue to smoke and 30% of all cancers are linked to tobacco use. Despite new smoking cessation pharmacotherapies, quit rates remain at less than 10%. A major lack of success is due to nicotine withdrawal symptomology. Current research suggests glial immune responses in the brain and subsequent neuroinflammation may underlie the negative symptomology. While neuroinflammation and associated gliosis has been demonstrated to be a primary mediator of many neurological disorders, including in CNS trauma, ischemia, stroke, and neurodegenerative diseases, its role in nicotine dependence tobacco use disorder has not been investigated. The microglia as the resident immune cells of the brain respond to changes in the microenvironment and respond by polarization into proinflammatory and anti-inflammatory states. We postulate that attenuating microgliosis pharmacologically will reduce the anxiety-like responses during nicotine withdrawal. Using a mouse animal model of nicotine dependence, we will investigate pharmacological compounds possessing both structurally and mechanistically distinct mechanisms of action for inhibiting this inflammation. Attenuation of the microglial activation should reduce the anxiety-like behaviors occurring during nicotine withdrawal by ameliorating the neuroinflammatory response and altering the secreted effector molecules landscape. These changes will be probed behaviorally and molecularly, concentrating on microglial morphology, and effector molecule measurements (cytokine and chemokines) at both the gene and protein levels. Changes in microglial response and signaling will add clinically relevant insight into mechanisms for neuroinflammation as a target of nicotine use disorder. This innovative approach could expand the pharmacological toolbox for smoking cessation and reduce the 7 million people a year tobacco related death toll.