Chronic exposure to nicotine in tobacco products results in numerous health consequences (lung cancer, emphysema, hypertension, etc.) and accounts for over 6 million deaths per year. Relapse rates are high among those who attempt to quit smoking, and pharmacotherapies that seek to foster smoking cessation have limited effectiveness. Thus, there is a significant unmet need for more effective strategies to treat nicotine dependence. Nicotine exposure produces physical dependence, and the physical and/or emotional nicotine withdrawal symptoms ? as compared to the rewarding effects of nicotine ? are often the most important contributors to relapse. Unfortunately, few research studies have probed the important question of physical dependence and nicotine withdrawal mechanisms. Indeed, a critical gap in knowledge exists regarding our understanding of how chronic nicotine exposure establishes physical dependence and therefore makes smokers highly susceptible to relapse. In this project, we will use mouse models to study the medial habenula (MHB), a small brain area in the epithalamic region that has recently been implicated in nicotine withdrawal, and which expresses extraordinarily high levels of several types of nicotinic acetylcholine receptors (nAChRs). nAChRs mediate the psychoactive and addictive action of nicotine, and we intend to identify the relevant nAChRs and MHB circuits involved in nicotine dependence and withdrawal. Three independent and complementary AIMs are proposed, each of which probes a specific mechanistic aspect of the response to nicotine in the MHB.
In AIM 1, we will use biophysical and optical techniques to determine through what mechanisms acute nicotine differentially activates specific cell types in MHB.
In AIM 2, we will employ similar techniques to determine how chronic nicotine selectively enhances neuronal activity in a specific sub-circuit of the withdrawal pathway. Finally, in AIM 3, we will couple physiology techniques with a novel behavioral/systems approach to identify important MHB circuits involved in generating physical and/or emotional responses during nicotine withdrawal. Together, these AIMs will help us solve the problem of understanding how cessation of nicotine intake causes the brain to generate aversive physical and emotional withdrawal responses that inevitably lead to relapse. Solving this problem could lead to new strategies or drugs to foster smoking cessation.

Public Health Relevance

Addiction to tobacco products is exceedingly common in the United States, and nicotine withdrawal and subsequent relapse is a significant contributor to the addiction process. The goal of this project is to leverage our well-qualified research team, our innovative tools, and our incisive methods to identify mechanisms that support tobacco addiction. By identifying these mechanisms, our project will promote the development of new and more effective strategies to help people quit smoking.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Sorensen, Roger
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Yan, Yijin; Peng, Can; Arvin, Matthew C et al. (2018) Nicotinic Cholinergic Receptors in VTA Glutamate Neurons Modulate Excitatory Transmission. Cell Rep 23:2236-2244
Banala, Sambashiva; Arvin, Matthew C; Bannon, Nicholas M et al. (2018) Photoactivatable drugs for nicotinic optopharmacology. Nat Methods 15:347-350
Arias, Hugo R; Jin, Xiaotao; Feuerbach, Dominik et al. (2017) Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula. Int J Biochem Cell Biol 92:202-209