Microglial Activation and Associated NADPH Oxidase 2-Induced Reactive Oxygen Species in the Nucleus Accumbens Contributes to Anxiety-like Behavior during Nicotine Withdrawal Adewale Adeluyi1, Lindsey Guerin2, Luyi Zhou3, Linnea Freeman4, Sherine Chan5, Micheal Wyatt1, Jill Turner1* 1Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, South Carolina, USA; 2Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, USA; 3Department of Pharmacology, School of Medicine, Southern Illinois University, Springfield, Illinois, USA; 4Department of Biology, Furman University, Greenville, South Carolina, USA; 5Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA *Corresponding Author
Tobacco smoking is the leading cause of preventable morbidity and mortality globally. Medical and behavioral interventions developed to reduce smoking-related diseases and deaths have been limited by smokers' inability to quit smoking - about 80% of smokers attempting to quit, fail. Mounting evidences have suggested that withdrawal from nicotine, the additive compound in tobacco, during smoking cessation may lead to increased inflammatory responses and consequential oxidative load. While the role of oxidative stress in the pathogenesis of many neurological disorders is established, its contribution to the development of nicotine withdrawal symptoms, which drives smoking relapse, is unknown. To evaluate excessive production of reactive oxygen species (ROS) and its contribution to the development of anxiety-like behavior during nicotine withdrawal, mice treated for two weeks with either saline or nicotine prior to withdrawal were injected intraperitoneally with either vehicle or 150mg/kg/day N-acetylcysteine (NAC), pre-withdrawal (X1day), during withdrawal (X1day), and post-withdrawal (X2days). Open field (OF) test and Marble-burying test (MB) were conducted on mice 30 minutes after receiving NAC injection on first and second post-withdrawal day, respectively. In this experiment, we used NAC as an antioxidant tool, and we found that excessive ROS production and upregulation of inflammatory markers in the nucleus accumbens during withdrawal were attenuated by NAC treatment. A similar profile was observed specifically with NADPH oxidase 2 (Nox2) expression, implicating this molecule as the key producer of ROS during nicotine withdrawal. Further analysis suggested possible withdrawal-induced microglia activation, which previous studies have demonstrated to be associated with Nox2-induced ROS production. Finally, our behavioral studies showed that NAC-treated withdrawal mice displayed anxiolytic effects in both OF and MB task in contrast to untreated withdrawal mice. Altogether, our emerging evidence suggests that underlying microglial activation and associated Nox2-induced ROS in the nucleus accumbens drive anxiogenic behavior during nicotine withdrawal in mice. For the first time in nicotine addiction studies, we demonstrate that nicotine withdrawal induces oxidative stress, which may contribute to the development of anxiety-like behavior during smoking cessation, via activation of microglial-Nox2 pathway. Therefore, antioxidants targeting ROS production via this pathway may be promising compounds for smoking cessation therapeutics.
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